BR112016025153B1 - "IMIDAZO[4,5-C]QUINOLIN-2-ONE COMPOUNDS, PHARMACEUTICAL COMPOSITION AND THEIR USE IN THE TREATMENT OF CANCER - Google Patents

Abstract

IMIDAZO[4,5-C]QUINOLIN-2-ONE COMPOUNDS AND THEIR USE IN THE TREATMENT OF CANCER. The present invention generally relates to certain compounds of Formula (I) and their pharmaceutically acceptable salts, R1,N,R2,O,N,R3,R5,N,N,Q,O,N,R4 (I) wherein Q, R1, R2, R3, R4 and R5 have any of the meanings defined herein. The present invention also relates to the use of such compounds and their salts to treat or prevent ATM kinase mediated diseases, including cancer. The invention further relates to crystalline forms of the imidazo[4,5-c]quinolin-2-one compounds and their pharmaceutically acceptable salts; pharmaceutical compositions comprising such compounds and salts; kits including such compounds and salts; methods of producing such compounds and salts; intermediates useful in making such compounds and salts; and to methods of treating ATM kinase mediated diseases, including cancer, using such compounds and salts.

Description

field of invention

[001] The present invention generally relates to substituted imidazo[4,5-c]quinolin-2-one compounds and pharmaceutically acceptable salts thereof. These compounds and their pharmaceutically acceptable salts selectively modulate ataxia telangiectasia mutated ("ATM") kinase protein, and the invention therefore also relates to the use of such compounds and their salts to treat or prevent ATM kinase mediated diseases, including cancer. . The invention further relates to crystalline forms of substituted imidazo[4,5-c]quinolin-2-one compounds and their pharmaceutically acceptable salts; pharmaceutical compositions comprising such compounds and salts; kits comprising such compounds and salts; methods of producing such compounds and salts; intermediates useful in making such compounds and salts; and to methods of treating ATM kinase mediated diseases, including cancer, using such compounds and salts.

Background of the invention

[002] ATM kinase is a serine threonine kinase originally identified as the mutated gene product in ataxiatelangiectasia. The ataxia-telangiectasia gene is located on human chromosome 1 lq22-23 and encodes a large protein of about 350 kDa, which is characterized by the presence of a serine/threonine domain similar to phosphatidylinositol ("PI") 3 -kinase, flanked by the FRAP-ATM-TRRAP and FATC domains that modulate ATM kinase activity and function. ATM kinase has been identified as an important participant in the DNA damage response elicited by double-stranded breaks. It acts primarily on S/G2/M cell cycle transitions and replication fork collapse initiating cell cycle checkpoints, chromatin modification, HR repair and pro-survival signaling cascades in order to maintain cell integrity after DNA damage (Lavin, 2008).

[003] ATM kinase signaling can be broadly divided into two categories: a canonical pathway, which signals along with the Mrel 1-Rad50-NBS1 complex resulting from double-strand breaks, and activates the damage checkpoint to DNA, and several non-canonical activation modes, which are activated by other forms of cellular stress (Cremona et al., 2013).

[004] ATM kinase is rapidly and robustly activated in response to double-strand breaks and is reportedly capable of phosphorylating over 800 substrates (Matsuoka et al., 2007), coordinating multiple stress response pathways (Kurz and Lees Miller, 2004). ATM kinase is predominantly present in the cell nucleus in an inactive homodimeric form, but capable of autophosphorylation on Ser1981 after detecting a DNA double-stranded break (canonical pathway), leading to dissociation to a monomer with full kinase activity (Bakkenist et al. al., 2003). This event is critical for activation, and ATM phospho-Ser1981 is therefore a direct pharmacodynamic biomarker and patient selection for dependence on tumor pathway.

[005] ATM kinase responds to double-stranded breaks caused by common cancer treatments, such as ionizing radiation and topoisomerase-II inhibitors (doxorubicin, etoposide), but also topoisomerase-I inhibitors (eg, irinotecan and topotecan), via single-stranded to double-stranded conversion during replication. ATM kinase inhibition can potentiate the activity of any of these agents and, as a result, ATM kinase inhibitors are anticipated to be of utility in the treatment of cancer, for example, as rational combination partners for existing therapies.

[006] CN102372711A reports certain imidazo[4,5-c]quinolin-2-one compounds which are mentioned as dual inhibitors of PI 3-kinase α and mammalian rapamycin target kinase ("mTOR"). Among the compounds reported in CN102372711A are the following:

[007] Certain compounds reported in CN102372711A

[008] CN102399218A reports certain imidazo[4,5-c]quinolin-2-one compounds which are mentioned as inhibitors of PI 3-kinase α. Among the compounds reported in CN102399218A are the following:

[009] Certain compounds reported in CN102399218A

[0010] Although the compounds in CN102372711A and CN102399218A are reported to have activity against PI 3-kinase α and, in some cases, mTOR kinase, there is still a need to develop new compounds that are more effective against different kinase enzymes such as ATM kinase. Furthermore, there is a need for new compounds that act against certain kinase enzymes, such as ATM kinase, in a highly selective manner (ie, modulating ATM more effectively than other biological targets).

[0011] As demonstrated elsewhere in the specification (for example, in the cellular assays described in the experimental section), the compounds of the present invention in general possess very potent ATM kinase inhibitory activity, but much less potent activity against other tyrosine kinase enzymes , such as PI 3-kinase α, mTOR kinase, and ataxia-telangiectasia and Rad3-related protein ("ATR"). Therefore, the compounds of the present invention not only inhibit ATM kinase, but can be considered as highly selective ATM kinase inhibitors.

[0012] As a result of their highly selective nature, the compounds of the present invention are expected to be especially useful in the treatment of diseases in which ATM kinase is implicated (e.g., in the treatment of cancer), but when it is desirable minimize off-target effects or toxicity that could arise from inhibition of other tyrosine kinase enzymes, such as those of the PI class 3-kinase α, mTOR kinase and ATR kinase.

Summary of the Invention

[0013] Briefly, this invention describes, in part, a compound of Formula (I):

[0014] or its pharmaceutically acceptable salt, wherein:

[0015] Q is a cyclobutyl or cyclopentyl ring, each of which is optionally substituted with a hydroxy or methoxy group, or Q is an oxetanyl, tetrahydrofuranyl or oxanyl ring, each of which is optionally substituted with a methyl group;

[0016] R1 is methyl;

[0017] R2 is hydrogen or methyl; or R1 and R2 together form an azetidinyl, pyrrolidinyl or piperidinyl ring;

[0018] R3 is hydrogen or fluorine;

[0019] R4 is hydrogen or methyl; It is

[0020] R5 is hydrogen or fluorine.

[0021] This invention also describes, in part, a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable diluent or carrier.

[0022] This invention also describes, in part, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in therapy.

[0023] This invention also describes, in part, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer.

[0024] This invention also describes, in part, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in the manufacture of a medicament for the treatment of cancer.

[0025] This invention also describes, in part, a method of treating cancer in a warm-blooded animal in need of such treatment, which comprises administering to said warm-blooded animal a therapeutically effective amount of a compound of Formula (I ), or its pharmaceutically acceptable salt.

Brief Description of the drawings

[0026] Figure 1: Powder X-ray diffraction pattern of Form A of 8-[6-(3-dimethylaminopropoxy)pyridin-3-yl]-3-methyl-1-(oxan-4-yl)imidazo- [5,4-c]quinolin-2-one.

[0027] Figure 2: DSC thermogram of Form A of 8-[6-(3-dimethylaminopropoxy)pyridin-3-yl]-3-methyl-1-(oxan-4-yl)imidazo[5,4- c ]quinolin-2-one.

[0028] Figure 3: Inhibition of tumor growth in the mouse xenograft model by 8-[6-(3-dimethylaminopropoxy)-pyridin-3-yl]-1-(cis-3-methoxycyclobutyl)-3-methylimidazo[4 ,5-c]quinolin-2-one (Example 2) in combination with irinotecan.

[0029] Figure 4: Inhibition of tumor growth in the mouse xenograft model by 8-[6-(3-dimethylaminopropoxy)pyridin-3-yl]-3-methyl-1-(oxan-4-yl)imidazo [5,4-c]quinolin-2-one (Example 1) in combination with irinotecan.

[0030] Figure 5: Inhibition of tumor growth in the mouse xenograft model by 8-[6-(3-dimethylaminopropoxy)-pyridin-3-yl]-3-methyl-1-(oxan-4-yl)imidazo[ 5,4-c]quinolin-2-one (Example 1) in combination with olaparib.

Detailed description of illustrative modalities

[0031] Many embodiments of the invention are detailed throughout the specification, and will be evident in reading by a person skilled in the art. It should not be interpreted that the invention is limited to any of its specific embodiments.

[0032] In the first embodiment, a compound of Formula (I) is provided:

[0033] or its pharmaceutically acceptable salt, wherein:

[0034] Q is a cyclobutyl or cyclopentyl ring, each of which is optionally substituted with a hydroxy or methoxy group, or Q is an oxetanyl, tetrahydrofuranyl or oxanyl ring, each of which is optionally substituted with a methyl group;

[0035] R1 is methyl;

[0036] R2 is hydrogen or methyl; or R1 and R2 together form an azetidinyl, pyrrolidinyl or piperidinyl ring;

[0037] R3 is hydrogen or fluorine;

[0038] R4 is hydrogen or methyl; It is

[0039] R5 is hydrogen or fluorine.

[0040] The terms "cyclobutyl ring" and "cyclopentyl ring" refer to carbocyclic rings containing no heteroatoms. The 1-methoxycyclobut-3-yl and 3-methoxycyclobut-1-yl groups have the same structure, as shown below. 1-methoxycyclobut-3-yl/3-methoxycyclobut-1-yl

[0041] A cis-1-methoxy-cyclobut-3-yl group is equivalent to a cis-3-methoxy-cyclobut-1-yl group and has the following structure: cis-1-methoxycyclobut-3-yl/cis-3-methoxycyclobut-1-yl

[0042] The same conventions apply to other cyclobutyl groups, for example, 1-hydroxycyclobut-3-yl groups and 3-hydroxycyclobut-1-yl groups.

[0043] Similarly, 1-methoxycyclopent-3-yl groups and 3-methoxycyclopent-1-yl groups have the same structure, as shown below: 1-methoxycyclobut-3-yl/3-methoxycyclobut-1-yl

[0044] The term "oxetanyl ring" includes the oxetan-2-yl and oxetan-3-yl groups, the structures of which are shown below.

[0045] The term "tetrahydrofuranyl ring" includes the tetrahydrofuran-2-yl and tetrahydrofuran-3-yl groups, the structures of which are shown below.

[0046] The term "oxanyl ring" includes the oxan-2-yl, oxan-3-yl and oxan-4-yl groups, the structures of which are shown below.

[0047] In the structures above, the dashed line indicates the binding position of the relevant group.

[0048] An oxanyl ring may also be referred to as tetrahydropyranyl ring. Likewise, an oxan-4-yl ring may also be referred to as a tetrahydropyran-4-yl ring; an oxan-3-yl ring may also be referred to as a tetrahydropyran-3-yl ring and an oxan-2-yl ring as a tetrahydropyran-2-yl ring.

[0049] When it is mentioned that "R1 and R2 together form an azetidinyl, pyrrolidinyl or piperidinyl ring", it means that the R1 and R2 groups are joined via a carbon-carbon covalent bond and form an unsubstituted alkylene chain of the appropriate length for the corresponding ring. For example, when R1 and R2 together form a pyrrolidinyl ring, R1 and R2 together represent an unsubstituted butylene chain that is attached to the relevant nitrogen atom in Formula (I) at both terminal carbons.

[0050] When used, the term "optionally" means that the subsequent feature may or may not occur. As such, the use of the term "optionally" includes cases where the feature is present as well as cases where the feature is not present. For example, a group "optionally substituted with a methoxy group" includes groups with and without a methoxy substituent.

[0051] The term "substituted" means that one or more hydrogens (eg 1 or 2 hydrogens or alternatively 1 hydrogen) in the designated group are replaced by the indicated substituents (eg 1 or 2 substituents or alternatively 1 substituent), as long as any atoms carrying a substituent maintain an allowable valence. Combinations of substituents only encompass stable compounds and stable synthetic intermediates. "Stable" means that the relevant compound or intermediate is sufficiently robust to be isolated and have utility as a synthetic intermediate or an agent with potential therapeutic utility. If a group is not described as "substituted" or "optionally substituted", the group should be assumed to be unsubstituted (ie, that none of the hydrogens in the designated group have been replaced).

[0052] The term "pharmaceutically acceptable" is used to specify that an object (eg, a salt, dosage form, diluent, or vehicle) is suitable for use in patients. A list of examples of pharmaceutically acceptable salts can be found in the Handbook of Pharmaceutically Salts: Properties, Selection and Use, P. H. Stahl and C. G. Wermuth, editors, Weinheim/Zurich:Wiley-VCH/VHCA, 2002. A suitable pharmaceutically acceptable salt of a compound of Formula (I) is, for example, an acid addition salt. An acid addition salt of a compound of Formula (I) can be formed by bringing the compound into contact with a suitable inorganic or organic acid under conditions known to one skilled in the art. An acid addition salt may, for example, be formed using an inorganic acid selected from the group consisting of hydrochloric acid, hydrobromic acid, sulfuric acid and phosphoric acid. An acid addition salt may also be formed using an organic acid selected from the group consisting of trifluoroacetic acid, citric acid, maleic acid, oxalic acid, acetic acid, formic acid, benzoic acid, fumaric acid, succinic acid, tartaric acid, lactic acid, pyruvic acid, methanesulfonic acid, benzenesulfonic acid and para-toluenesulfonic acid.

[0053] Therefore, in one embodiment, there is provided a compound of Formula (I) or a pharmaceutically acceptable salt thereof, wherein the pharmaceutically acceptable salt is a salt of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, trifluoroacetic acid, citric acid, maleic acid, oxalic acid, acetic acid, formic acid, benzoic acid, fumaric acid, succinic acid, tartaric acid, lactic acid, pyruvic acid, methanesulfonic acid, benzenesulfonic acid or para-toluenesulfonic acid. In one embodiment, there is provided a compound of Formula (I) or a pharmaceutically acceptable salt thereof, wherein the pharmaceutically acceptable salt is a salt of trifluoroacetic acid, formic acid or methanesulfonic acid. In one embodiment, there is provided a compound of Formula (I) or a pharmaceutically acceptable salt thereof, wherein the pharmaceutically acceptable salt is a trifluoroacetic acid or methanesulfonic acid salt. In one embodiment, there is provided a compound of Formula (I) or a pharmaceutically acceptable salt thereof, wherein the pharmaceutically acceptable salt is a methanesulfonic acid salt. In one embodiment, there is provided a compound of Formula (I) or a pharmaceutically acceptable salt thereof, wherein the pharmaceutically acceptable salt is a mono-methanesulfonic acid salt, i.e., the compound stoichiometry of the compound of Formula (I) for methanesulfonic acid it is 1:1.

[0054] An additional embodiment provides any of the embodiments defined herein (e.g., the embodiment of claim 1), with the proviso that one or more specific Examples (e.g., one, two, or three specific Examples) selected from the group consisting of Examples 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51,52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70 and 71 are individually waived.

[0055] Some variable group values in Formula (I) are as follows. Such values may be used in combination with any of the definitions, claims (eg claim 1) or embodiments defined herein to provide further embodiments.

[0056] a) Q is a cyclobutyl or cyclopentyl ring, each of which is substituted with a hydroxy or methoxy group, or Q is an oxetanyl, tetrahydrofuranyl or oxanyl ring, each of which is optionally substituted with a methyl group.

[0057] b) Q is a cyclobutyl ring substituted with a hydroxy or methoxy group, or Q is an oxetanyl or oxanyl ring, each of which is optionally substituted with a methyl group.

[0058] c) Q is a cyclobutyl ring substituted with a hydroxy or methoxy group, or Q is an oxetanyl or oxanyl ring.

[0059] d) Q is cyclobutyl, 1-methoxy-cyclobut-3-yl, 1-hydroxy-cyclobut-3-yl, 3-methoxycyclopent-1-yl, oxetan-3-yl, tetrahydrofuran-3-yl , oxan-3-yl, oxan-4-yl or 4-methyloxan-4-yl.

[0060] e) Q is 1-methoxy-cyclobut-3-yl, 1-hydroxy-cyclobut-3-yl, 3-methoxycyclopent-1-yl, oxetan-3-yl, oxan-3-yl, oxan-4 -yl or 4-methyloxan-4-yl.

[0061] f) Q is 1-methoxy-cyclobut-3-yl, 1-hydroxy-cyclobut-3-yl or oxan-4-yl.

[0062] g) Q is cis-1-methoxy-cyclobut-3-yl or oxan-4-yl.

[0063] h) Q is a cyclobutyl or cyclopentyl ring, each of which is optionally substituted by a hydroxy or methoxy group.

[0064] i) Q is a cyclobutyl or cyclopentyl ring, each of which is optionally substituted with a methoxy group.

[0065] j) Q is a cyclobutyl ring substituted with a hydroxy or methoxy group.

[0066] k) Q is cyclobutyl, 1-hydroxy-cyclobut-3-yl or 1-methoxy-cyclobut-3-yl.

[0067] l) Q is cyclobutyl.

[0068] m) Q is a cyclopentyl ring substituted with a hydroxy or methoxy group.

[0069] n) Q is a cyclopentyl ring substituted with a methoxy group.

[0070] o) Q is 3-methoxycyclopent-1-yl.

[0071] p) Q is 1-hydroxy-cyclobut-3-yl or 1-methoxy-cyclobut-3-yl.

[0072] q) Q is cis-1-hydroxy-cyclobut-3-yl or cis-1-methoxy-cyclobut-3-yl.

[0073] r) Q is cis-1-methoxy-cyclobut-3-yl.

[0074] s) Q is an oxetanyl, tetrahydrofuranyl or oxanyl ring, each of which is optionally substituted with a methyl group.

[0075] t) Q is an oxetanyl or oxanyl ring, each of which is optionally substituted with a methyl group.

[0076] u) Q is an oxetanyl or tetrahydrofuranyl ring.

[0077] v) Q is an oxetanyl ring.

[0078] w) Q is oxetan-3-yl.

[0079] x) Q is a tetrahydrofuranyl ring.

[0080] y) Q is tetrahydrofuran-3-yl.

[0081] z) Q is an oxanyl ring optionally substituted with a methyl group.

[0082] aa) Q is an oxanyl ring.

[0083] bb) Q is oxan-4-yl.

[0084] cc) R1 is methyl.

[0085] dd) R2 is methyl.

[0086] and e) R2 is hydrogen.

[0087] ff) R1 is methyl and R2 is hydrogen or methyl.

[0088] gg) R1 and R2 are both methyl; or R1 and R2 together form a pyrrolidinyl ring.

[0089] hh) R1 and R2 are both methyl.

[0090] ii) R1 and R2 together form an azetidinyl, pyrrolidinyl or piperidinyl ring.

[0091] jj) R1 and R2 together form an azetidinyl ring.

[0092] kk) R1 and R2 together form a pyrrolidinyl ring.

[0093] ll) R1 and R2 together form a piperidinyl ring.

[0094] mm) R3 and R5 are both hydrogen.

[0095] nn) R3 is hydrogen.

[0096] oo) R3 is fluorine.

[0097] pp) R4 is hydrogen.

[0098] qq) R4 is methyl.

[0099] rr) R5 is hydrogen.

[00100] ss) R5 is fluorine.

[00101] In one embodiment, there is provided a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in which:

[00102] Q is cyclobutyl, 1-methoxy-cyclobut-3-yl, 1-hydroxy-cyclobut-3-yl, 3-methoxycyclopent-1-yl, oxetan-3-yl, tetrahydrofuran-3-yl, oxan -3-yl, oxan-4-yl or 4-methyloxan-4-yl;

[00103] R1 is methyl;

[00104] R2 is hydrogen or methyl; or R1 and R2 together form an azetidinyl, pyrrolidinyl or piperidinyl ring;

[00105] R3 is hydrogen or fluorine;

[00106] R4 is hydrogen or methyl; It is

[00107] R5 is hydrogen or fluorine.

[00108] In one embodiment, there is provided a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in which:

[00109] Q is 1-methoxy-cyclobut-3-yl, 1-hydroxy-cyclobut-3-yl, 3-methoxycyclopent-1-yl, oxetan-3-yl, oxan-3-yl, oxan-4-yl or 4-methyloxan-4-yl;

[00110] R1 is methyl;

[00111] R2 is hydrogen or methyl; or R1 and R2 together form an azetidinyl, pyrrolidinyl or piperidinyl ring;

[00112] R3 is hydrogen or fluorine;

[00113] R4 is hydrogen or methyl; It is

[00114] R5 is hydrogen or fluorine.

[00115] In one embodiment, a compound of Formula (I) is provided, in which:

[00116] Q is 1-methoxy-cyclobut-3-yl, 1-hydroxy-cyclobut-3-yl or 3-methoxycyclopent-1-yl;

[00117] R1 is methyl;

[00118] R2 is hydrogen or methyl; or R1 and R2 together form an azetidinyl, pyrrolidinyl or piperidinyl ring;

[00119] R3 is hydrogen or fluorine;

[00120] R4 is hydrogen or methyl; It is

[00121] R5 is hydrogen or fluorine.

[00122] In one embodiment, there is provided a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in which:

[00123] Q is oxetan-3-yl, oxan-3-yl, oxan-4-yl or 4-methyloxan-4-yl;

[00124] R1 is methyl;

[00125] R2 is hydrogen or methyl; or R1 and R2 together form an azetidinyl, pyrrolidinyl or piperidinyl ring;

[00126] R3 is hydrogen or fluorine;

[00127] R4 is hydrogen or methyl; It is

[00128] R5 is hydrogen or fluorine.

[00129] In one embodiment, there is provided a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in which:

[00130] Q is cis-1-methoxy-cyclobut-3-yl or oxan-4-yl;

[00131] R1 is methyl;

[00132] R2 is methyl or hydrogen;

[00133] R3 is hydrogen;

[00134] R4 is methyl or hydrogen; It is

[00135] R5 is hydrogen.

[00136] In one embodiment, there is provided a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of:

[00137] 8-[6-(3-dimethylaminopropoxy)pyridin-3-yl]-3-methyl-1-(oxan-4-yl)imidazo[5,4-c]quinolin-2-one;

[00138] 8-[6-(3-dimethylaminopropoxy)pyridin-3-yl]-1-(cis-3-methoxycyclobutyl)-3-methylimidazo[4,5-c]quinolin-2-one;

[00139] 8-[6-(3-dimethylaminopropoxy)pyridin-3-yl]-7-fluoro-3-methyl-1-(4-methyloxan-4-yl)imidazo[5,4-c]quinolin-2 -one;

[00140] 8-[6-(3-dimethylaminopropoxy)pyridin-3-yl]-3-methyl-1-(oxetan-3-yl)imidazo[5,4-c]quinolin-2-one;

[00141] 8-[6-(3-dimethylaminopropoxy)pyridin-3-yl]-1-(cis-3-hydroxycyclobutyl)-3-methylimidazo[4,5-c]quinolin-2-one;

[00142] 8-[6-(3-dimethylaminopropoxy)pyridin-3-yl]-7-fluoro-1-(cis-3-methoxycyclobutyl)-3-methylimidazo[4,5-c]quinolin-2-one;

[00143] 8-[6-(3-dimethylaminopropoxy)pyridin-3-yl]-3-methyl-1-(4-methyloxan-4-yl)imidazo[5,4-c]quinolin-2-one;

[00144] 8-[6-(3-dimethylaminopropoxy)pyridin-3-yl]-7-fluoro-3-methyl-1-(oxan-4-yl)imidazo[5,4-c]quinolin-2-one ;

[00145] 8-[6-(3-dimethylaminopropoxy)pyridin-3-yl]-7-fluoro-3-methyl-1-(oxetan-3-yl)imidazo[5,4-c]quinolin-2-one ;

[00146] 8-[6-(3-dimethylaminopropoxy)pyridin-3-yl]-7-fluoro-3-methyl-1-[(3R)-oxan-3-yl]imidazo[5,4-c]quinoline -2-one;

[00147] 8-[6-(3-dimethylaminopropoxy)pyridin-3-yl]-7-fluoro-3-methyl-1-[(3S)-oxan-3-yl]imidazo[5,4-c]quinoline -2-one;

[00148] 8-[6-(3-dimethylaminopropoxy)pyridin-3-yl]-1-(cis-3-methoxycyclobutyl)-3H-imidazo[4,5-c]quinolin-2-one;

[00149] 8-[6-(3-dimethylaminopropoxy)pyridin-3-yl]-1-(oxan-4-yl)-3H-imidazo[4,5-c]quinolin-2-one;

[00150] 8-[6-[3-(azetidin-1-yl)propoxy]pyridin-3-yl]-1-(cis-3-hydroxycyclobutyl)-3-methylimidazo[4,5-c]quinolin-2 -one;

[00151] 1-(3-cis-hydroxycyclobutyl)-3-methyl-8-[6-(3-pyrrolidin-1-ylpropoxy)pyridin-3-yl]imidazo[4,5-c]quinolin-2-one ;

[00152] 8-[6-(3-dimethylaminopropoxy)pyridin-3-yl]-3-methyl-1-[(3R)-oxan-3-yl]imidazo[5,4-c]quinolin-2-one ;

[00153] 8-[6-(3-dimethylaminopropoxy)pyridin-3-yl]-3-methyl-1-[(3S)-oxan-3-yl]imidazo[5,4-c]quinolin-2-one ;

[00154] 8-[6-(3-dimethylaminopropoxy)-2-fluoropyridin-3-yl]-1-(cis-3-methoxycyclobutyl)-3-methylimidazo[4,5-c]quinolin-2-one;

[00155] 8-[6-(3-dimethylaminopropoxy)-2-fluoropyridin-3-yl]-7-fluoro-1-(cis-3-methoxycyclobutyl)-3-methylimidazo[4,5-c]quinolin-2 -one;

[00156] 8-[6-(3-dimethylaminopropoxy)-2-fluoropyridin-3-yl]-3-methyl-1-[(3S)-oxan-3-yl]imidazo[5,4-c]quinolin- 2-one;

[00157] 8-[6-(3-dimethylaminopropoxy)-2-fluoropyridin-3-yl]-3-methyl-1-(oxan-4-yl)imidazo[5,4-c]quinolin-2-one;

[00158] 8-[6-(3-dimethylaminopropoxy)-2-fluoropyridin-3-yl]-3-methyl-1-[(3R)-oxan-3-yl]imidazo[5,4-c]quinolin- 2-one;

[00159] 7-Fluoro-3-methyl-8-[6-(3-pyrrolidin-1-ylpropoxy)-3-pyridyl]-1-[(3S)-tetrahydropyran-3-yl]imidazo[4, 5-c]quinolin-2-one;

[00160] 7-Fluoro-3-methyl-8-[6-(3-pyrrolidin-1-ylpropoxy)-3-pyridyl]-1-[(3S)-tetrahydropyran-3-yl]imidazo[4, 5-c]quinolin-2-one;

[00161] 8-[6-(3-dimethylaminopropoxy)pyridin-3-yl]-1-[(1R,3R)-3-methoxycyclopentyl]-3-methylimidazo[4,5-c]quinolin-2-one;

[00162] 8-[6-(3-dimethylaminopropoxy)pyridin-3-yl]-1-[(1S,3S)-3-methoxycyclopentyl]-3-methylimidazo[4,5-c]quinolin-2-one;

[00163] 7-Fluoro-1-(cis-3-methoxycyclobutyl)-3-methyl-8-[6-(3-pyrrolidin-1-ylpropoxy)pyridin-3-yl]imidazo[4,5-c]quinoline -2-one;

[00164] 1-(cis-3-methoxycyclobutyl)-3-methyl-8-[6-(3-pyrrolidin-1-ylpropoxy)pyridin-3-yl]imidazo[4,5-c]quinolin-2-one ;

[00165] 3-Methyl-1-[(3S)-oxan-3-yl]-8-[6-(3-pyrrolidin-1-ylpropoxy)pyridin-3-yl]imidazo[5,4-c]quinoline -2-one;

[00166] 3-Methyl-1-(oxan-4-yl)-8-[6-(3-pyrrolidin-1-ylpropoxy)pyridin-3-yl]imidazo[5,4-c]quinolin-2-one ;

[00167] 3-Methyl-1-[(3S)-oxan-3-yl]-8-[6-(3-piperidin-1-ylpropoxy)pyridin-3-yl]imidazo[5,4-c]quinoline -2-one;

[00168] 3-Methyl-1-[(3R)-oxan-3-yl]-8-[6-(3-piperidin-1-ylpropoxy)pyridin-3-yl]imidazo[5,4-c]quinoline -2-one;

[00169] 1-(cis-3-methoxycyclobutyl)-3-methyl-8-[6-(3-piperidin-1-ylpropoxy)pyridin-3-yl]imidazo[4,5-c]quinolin-2-one ;

[00170] 8-[6-[3-(azetidin-1-yl)propoxy]pyridin-3-yl]-3-methyl-1-[(3R)-oxan-3-yl]imidazo[5,4- c]quinolin-2-one;

[00171] 1-(cis-3-methoxycyclobutyl)-8-[6-(3-pyrrolidin-1-ylpropoxy)pyridin-3-yl]-3H-imidazo[4,5-c]quinolin-2-one;

[00172] 1-(oxan-4-yl)-8-[6-(3-piperidin-1-ylpropoxy)pyridin-3-yl]-3H-imidazo[4,5-c]quinolin-2-one;

[00173] 3-Methyl-1-(oxan-4-yl)-8-[6-(3-piperidin-1-ylpropoxy)pyridin-3-yl]imidazo[5,4-c]quinolin-2-one ;

[00174] 8-[6-[3-(azetidin-1-yl)propoxy]pyridin-3-yl]-1-(cis-3-methoxycyclobutyl)-3-methylimidazo[4,5-c]quinolin-2 -one;

[00175] 8-[6-[3-(azetidin-1-yl)propoxy]pyridin-3-yl]-3-methyl-1-(oxan-4-yl)imidazo[5,4-c]quinolin- 2-one;

[00176] 3-Methyl-8-[6-(3-methylaminopropoxy)pyridin-3-yl]-1-(oxan-4-yl)imidazo[5,4-c]quinolin-2-one;

[00177] 3-Methyl-8-[6-(3-methylaminopropoxy)pyridin-3-yl]-1-[(3S)-oxan-3-yl]imidazo[5,4-c]quinolin-2-one ; It is

[00178] 1-(cis-3-methoxycyclobutyl)-3-methyl-8-[6-(3-methylaminopropoxy)pyridin-3-yl]imidazo[4,5-c]quinolin-2-one;

[00179] 3-Methyl-8-[6-[3-(methylamino)propoxy]-3-pyridyl]-1-[(3R)-tetrahydropyran-3-yl]imidazo[4,5-c]quinoline -2-one;

[00180] 8-[6-[3-(dimethylamino)propoxy]-3-pyridyl]-3-methyl-1-[(3R)-tetrahydrofuran-3-yl]imidazo[4,5-c]quinoline -2-one;

[00181] 8-[6-[3-(dimethylamino)propoxy]-3-pyridyl]-3-methyl-1-[(3S)-tetrahydrofuran-3-yl]imidazo[4,5-c]quinoline -2-one;

[00182] 1-Cyclobutyl-8-[6-[3-(dimethylamino)propoxy]-3-pyridyl]-3-methyl-imidazo[4,5-c]quinolin-2-one;

[00183] 7-Fluoro-3-methyl-8-[6-[3-(1-piperidyl)propoxy]-3-pyridyl]-1-[(3S)-tetrahydropyran-3-yl]imidazo[4 ,5-c]quinolin-2-one;

[00184] 8-[6-[3-(dimethylamino)propoxy]-2-fluoro-3-pyridyl]-7-fluoro-3-methyl-1-[(3S)-tetrahydropyran-3-yl]imidazo [4,5-c]quinolin-2-one;

[00185] 8-[6-[3-(dimethylamino)propoxy]-2-fluoro-3-pyridyl]-3-methyl-1-[(3S)-tetrahydrofuran-3-yl]imidazo[4.5 -c]quinolin-2-one;

[00186] 8-[6-[3-(dimethylamino)propoxy]-2-fluoro-3-pyridyl]-3-methyl-1-[(3R)-tetrahydrofuran-3-yl]imidazo[4.5 -c]quinolin-2-one;

[00187] 1-Cyclobutyl-8-[6-[3-(dimethylamino)propoxy]-2-fluoro-3-pyridyl]-3-methyl-imidazo[4,5-c]quinolin-2-one;

[00188] 8-[6-[3-(dimethylamino)propoxy]-2-fluoro-3-pyridyl]-3-methyl-1-(oxetan-3-yl)imidazo[4,5-c]quinolin-2 -one;

[00189] 7-Fluoro-3-methyl-8-[6-[3-(1-piperidyl)propoxy]-3-pyridyl]-1-tetrahydropyran-4-yl-imidazo[4,5-c] quinolin-2-one;

[00190] 3-Methyl-8-[6-[3-(1-piperidyl)propoxy]-3-pyridyl]-1-[(3R)-tetrahydrofuran-3-yl]imidazo[4,5-c ]quinolin-2-one;

[00191] 3-Methyl-8-[6-[3-(1-piperidyl)propoxy]-3-pyridyl]-1-[(3S)-tetrahydrofuran-3-yl]imidazo[4,5-c ]quinolin-2-one;

[00192] 3-Methyl-1-(oxetan-3-yl)-8-[6-[3-(1-piperidyl)propoxy]-3-pyridyl]imidazo[4,5-c]quinolin-2-one ;

[00193] 1-Cyclobutyl-3-methyl-8-[6-[3-(1-piperidyl)propoxy]-3-pyridyl]imidazo[4,5-c]quinolin-2-one;

[00194] 1-Cyclobutyl-3-methyl-8-[6-(3-pyrrolidin-1-ylpropoxy)-3-pyridyl]imidazo[4,5-c]quinolin-2-one;

[00195] 3-Methyl-8-[6-(3-pyrrolidin-1-ylpropoxy)-3-pyridyl]-1-[(3R)-tetrahydropyran-3-yl]imidazo[4,5-c] quinolin-2-one;

[00196] 8-[6-[3-(azetidin-1-yl)propoxy]-3-pyridyl]-3-methyl-1-[(3S)-tetrahydropyran-3-yl]imidazo[4.5 -c]quinolin-2-one;

[00197] 8-[2-Fluoro-6-(3-pyrrolidin-1-ylpropoxy)-3-pyridyl]-3-methyl-1-[(3S)-tetrahydropyran-3-yl]imidazo[4, 5-c]quinolin-2-one;

[00198] 8-[6-[3-(dimethylamino)propoxy]-3-pyridyl]-7-fluoro-1-[(1R,3R)-3-methoxycyclopentyl]-3-methyl-imidazo[4,5- c]quinolin-2-one;

[00199] 8-[6-[3-(dimethylamino)propoxy]-3-pyridyl]-7-fluoro-1-[(1S,3S)-3-methoxycyclopentyl]-3-methyl-imidazo[4,5- c]quinolin-2-one;

[00200] 1-[(1R,3R)-3-methoxycyclopentyl]-3-methyl-8-[6-[3-(1-piperidyl)propoxy]-3-pyridyl]imidazo[4,5-c]quinoline -2-one;

[00201] 1-[(1S,3S)-3-methoxycyclopentyl]-3-methyl-8-[6-[3-(1-piperidyl)propoxy]-3-pyridyl]imidazo[4,5-c]quinoline -2-one;

[00202] 1-[(1S,3S)-3-methoxycyclopentyl]-3-methyl-8-[6-(3-pyrrolidin-1-ylpropoxy)-3-pyridyl]imidazo[4,5-c]quinolin- 2-one;

[00203] 1-[(1R,3R)-3-methoxycyclopentyl]-3-methyl-8-[6-(3-pyrrolidin-1-ylpropoxy)-3-pyridyl]imidazo[4,5-c]quinolin- 2-one;

[00204] 8-[6-[3-(dimethylamino)propoxy]-2-fluoro-3-pyridyl]-1-[(1R,3R)-3-methoxycyclopentyl]-3-methyl-imidazo[4,5- c]quinolin-2-one;

[00205] 8-[6-[3-(dimethylamino)propoxy]-2-fluoro-3-pyridyl]-1-[(1S,3S)-3-methoxycyclopentyl]-3-methyl-imidazo[4,5- c]quinolin-2-one;

[00206] 8-[6-[3-(dimethylamino)propoxy]-3-pyridyl]-7-fluoro-1-[(1R,3S)-3-methoxycyclopentyl]-3-methyl-imidazo[4,5- c]quinolin-2-one; It is

[00207] 8-[6-[3-(dimethylamino)propoxy]-3-pyridyl]-7-fluoro-1-[(1S,3R)-3-methoxycyclopentyl]-3-methyl-imidazo[4,5- c]quinolin-2-one.

[00208] In one embodiment, a compound of Formula (I) or a pharmaceutically acceptable salt thereof is provided, wherein the compound is selected from the group consisting of:

[00209] 8-[6-(3-dimethylaminopropoxy)pyridin-3-yl]-1-[(1R,3R)-3-methoxycyclopentyl]-3-methylimidazo[4,5-c]quinolin-2-one; It is

[00210] 8-[6-(3-Dimethylaminopropoxy)pyridin-3-yl]-1-[(1S,3S)-3-methoxycyclopentyl]-3-methylimidazo[4,5-c]quinolin-2-one.

[00211] In one embodiment, 8-[6-(3-dimethylaminopropoxy)pyridin-3-yl]-1-(cis-3-methoxycyclobutyl)-3-methylimidazo[4,5-c]quinolin-2- is provided one, or its pharmaceutically acceptable salt.

[00212] In one embodiment, 8-[6-(3-dimethylaminopropoxy)pyridin-3-yl]-1-(cis-3-methoxycyclobutyl)-3-methylimidazo[4,5-c]quinolin-2- is provided ona.

[00213] In one embodiment, a pharmaceutically acceptable salt of 8-[6-(3-dimethylaminopropoxy)pyridin-3-yl]-1-(cis-3-methoxycyclobutyl)-3-methylimidazo[4,5-c] is provided ]quinolin-2-one.

[00214] In one embodiment, 8-[6-(3-dimethylaminopropoxy)pyridin-3-yl]-3-methyl-1-(oxan-4-yl)imidazo[5,4-c]quinolin-2 is provided -one, or its pharmaceutically acceptable salt.

[00215] In one embodiment, 8-[6-(3-dimethylaminopropoxy)pyridin-3-yl]-3-methyl-1-(oxan-4-yl)imidazo[5,4-c]quinolin-2 is provided -ona.

[00216] In one embodiment, a pharmaceutically acceptable salt of 8-[6-(3-dimethylaminopropoxy)pyridin-3-yl]-3-methyl-1-(oxan-4-yl)imidazo[5,4- c]quinolin-2-one.

[00217] In one embodiment, 1-(cis-3-methoxycyclobutyl)-3-methyl-8-{6-[3-(pyrrolidin-1-yl)propoxy]pyridin-3-yl}-1,3 is provided -dihydro-2H-imidazo[4,5-c]quinolin-2-one, or its pharmaceutically acceptable salt.

[00218] In one embodiment, 1-(cis-3-methoxycyclobutyl)-3-methyl-8-{6-[3-(pyrrolidin-1-yl)propoxy]pyridin-3-yl}-1,3 is provided -dihydro-2H-imidazo[4,5-c]quinolin-2-one.

[00219] In one embodiment, a pharmaceutically acceptable salt of 1-(cis-3-methoxycyclobutyl)-3-methyl-8-{6-[3-(pyrrolidin-1-yl)propoxy]pyridin-3-yl is provided }-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-one.

[00220] The compounds and salts described in this specification may exist in solvated and unsolvated forms. For example, a solvated form can be a hydrated form, such as the hemihydrate, monohydrate, dihydrate, trihydrate, or an alternate amount thereof. The invention encompasses all such solvated and unsolvated forms of compounds of Formula (I), especially insofar as such forms possess ATM kinase inhibitory activity, as, for example, measured using the tests described herein.

[00221] The atoms of compounds and salts described in this specification may exist as their isotopes. The invention encompasses all compounds of Formula (I) in which one atom is replaced by one or more of its isotopes (e.g. a compound of Formula (I) when one or more carbon atoms is an 11C or 13C isotope of carbon , when one or more of the hydrogen atoms is a 2H or 3H isotope or when one or more of the fluorine atoms is an 18F isotope).

[00222] The compounds and salts described in this specification may exist as a mixture of tautomers. "Tautomers" are structural isomers that exist in equilibrium and result from the migration of a hydrogen atom. The invention includes all tautomers of compounds of Formula (I), especially insofar as such tautomers possess ATM kinase inhibitory activity.

[00223] The compounds and salts described in this specification may exist in optically active or racemic forms due to the presence of one or more asymmetric carbon atoms. The invention includes any optically active or racemic form of a compound of Formula (I) which possesses ATM kinase inhibitory activity, as, for example, measured using the tests described herein. Synthesis of optically active forms can be carried out by standard techniques of organic chemistry which are well known in the art, for example by synthesis of optically active materials or by resolution of a racemic form.

[00224] Therefore, in one embodiment, there is provided a compound of Formula (I), or a pharmaceutically acceptable salt thereof, which is a single optical isomer that is in enantiomeric excess (%ee) > 95%, > 98% or > 99 %. In one embodiment, the single optical isomer is present in enantiomeric excess (%ee) > 99%.

[00225] The compounds and salts described in this specification may be crystalline, and may exhibit one or more crystalline forms. The invention encompasses any crystalline or amorphous form of a compound of Formula (I), or mixture of such forms, which possesses ATM kinase inhibitory activity.

[00226] It is generally known that crystalline materials can be characterized using conventional techniques such as X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC), thermogravimetric analysis (TGA). Fourier transform infrared diffuse reflectance spectroscopy (DRIFT). Near Infrared Spectroscopy (NIR). Nuclear magnetic resonance spectroscopy in solution and/or solid state. The water content of such crystalline materials can be determined by Karl Fischer analysis.

[00227] The specific solid shapes described herein provide XRPD patterns substantially equal to the XRPD patterns shown in the Figures, and have the various 2-theta values shown in the Tables included herein. The person skilled in the art will understand that an XRPD or diffractogram pattern can be obtained with one or more measurement errors, depending on the recording conditions, such as the equipment or machine used. Likewise, it is generally known that intensities in an XRPD pattern can fluctuate depending on measurement conditions or sample preparation, as a result of a preferred direction. Those skilled in the art of XRPD will further realize that the relative intensity of peaks can also be affected by, for example, grains over 30 µm in size and non-unitary screen ratios. The person skilled in the art understands that the position of reflections can be affected by the precise height at which the sample sits on the diffractometer, and also by the zero calibration of the diffractometer. Sample surface planarity may also have a small effect.

[00228] As a result of these considerations, the diffraction pattern data presented should not be considered as absolute values (Jenkins, R & Snyder, R.L. "Introduction to X-Ray Powder Diffractometry"' John Wiley & Sons 1996; Bunn, C.W. ( 1948), "Chemical Crystallography", Clarendon Press, London; Klug, H. P. & Alexander, L. E. (1974), "X-Ray Diffraction Procedures"). It should be correspondingly understood that solid forms are not limited to crystals that provide XRPD patterns that are identical to the XRPD pattern shown in the Figures, and any crystals that provide XRPD patterns substantially the same as those shown in the Figures fall within the scope of the invention. A person skilled in the art of XRPD is able to judge the substantial identity of XRPD patterns. In general, an error in measuring a diffraction angle in an XRPD is approximately plus or minus 0.2° 2-theta, and this degree of measurement error must be taken into account when considering the diffraction pattern of powder X-rays in the Figures and when reading the data contained in the Tables below.

[00229] The compound of Example 1 exhibits crystalline properties, and a crystalline form has been characterized.

[00230] Therefore, in one embodiment, Form A of 8-[6-(3-dimethylaminopropoxy)pyridin-3-yl]-3-methyl-1-(oxan-4-yl)imidazo[5,4] is provided - c]quinolin-2-one.

[00231] In one embodiment, a crystalline form is provided, Form A of 8-[6-(3-dimethylaminopropoxy)pyridin-3-yl]-3-methyl-1-(oxan-4-yl)imidazo[5, 4-c]quinolin-2-one, which has an X-ray powder diffraction pattern with at least one specific peak at approximately 2-theta = 3.9°.

[00232] In one embodiment, a crystalline form is provided, Form A of 8-[6-(3-dimethylaminopropoxy)pyridin-3-yl]-3-methyl-1-(oxan-4-yl)imidazo[5, 4-c]quinolin-2-one, which has an X-ray powder diffraction pattern with at least one specific peak at approximately 2-theta = 11.6°.

[00233] In one embodiment, a crystalline form is provided, Form A of 8-[6-(3-dimethylaminopropoxy)pyridin-3-yl]-3-methyl-1-(oxan-4-yl)imidazo[5, 4-c]quinolin-2-one, which has an X-ray powder diffraction pattern with at least two specific peaks at approximately 2-theta = 3.9 and 11.6°.

[00234] In one embodiment, a crystalline form is provided, Form A of 8-[6-(3-dimethylaminopropoxy)pyridin-3-yl]-3-methyl-1-(oxan-4-yl)imidazo[5, 4-c]quinolin-2-one, which has an X-ray powder diffraction pattern with specific peaks at approximately 2-theta = 3.9; 7.7; 10.7; 11.6; 15.4; 16.9; 17.4; 18.4; 21.3 and 22.2°.

[00235] In one embodiment, a crystalline form, Form A of 8-[6-(3-dimethylaminopropoxy)pyridin-3-yl]-3-methyl-1-(oxan-4-yl)imidazo[5, is provided 4-c]quinolin-2-one which has an X-ray powder diffraction pattern substantially the same as the X-ray powder diffraction pattern shown in Figure 1.

[00236] In one embodiment, a crystalline form is provided, Form A of 8-[6-(3-dimethylaminopropoxy)pyridin-3-yl]-3-methyl-1-(oxan-4-yl)imidazo[5, 4-c]quinolin-2-one, which has an X-ray powder diffraction pattern with at least one specific peak at 2-theta = 3.9° plus or minus 0.2° 2-theta.

[00237] In one embodiment, a crystalline form is provided, Form A of 8-[6-(3-dimethylaminopropoxy)pyridin-3-yl]-3-methyl-1-(oxan-4-yl)imidazo[5, 4-c]quinolin-2-one, which has an X-ray powder diffraction pattern with at least one specific peak at 2-theta = 11.6° plus or minus 0.2° 2-theta.

[00238] In one embodiment, a crystalline form is provided, Form A of 8-[6-(3-dimethylaminopropoxy)pyridin-3-yl]-3-methyl-1-(oxan-4-yl)imidazo[5, 4-c]quinolin-2-one, which has an X-ray powder diffraction pattern with at least two specific peaks at 2-theta = 3.9 and 11.6° plus or minus 0.2° 2-theta .

[00239] In one embodiment, a crystalline form is provided, Form A of 8-[6-(3-dimethylaminopropoxy)pyridin-3-yl]-3-methyl-1-(oxan-4-yl)imidazo[5, 4-c]quinolin-2-one, which has an X-ray powder diffraction pattern with specific peaks at 2-theta = 3.9; 7.7; 10.7; 11.6; 15.4; 16.9; 17.4; 18.4; 21.3 and 22.2° plus or minus 0.2° 2-theta.

[00240] DSC analysis of Form A of 8-[6-(3-dimethylaminopropoxy)pyridin-3-yl]-3-methyl-1-(oxan-4-yl)imidazo[5,4-c]quinoline -2-one shows a melting endotherm starting at 212.3 °C and peaking at 214.1 °C (Figure 2).

[00241] A person skilled in the art understands that the value or range of values observed in the DSC thermogram of a given compound will show variation between lots of different purities. Therefore, while for one compound the range may be small, for others the range may be quite large. In general, a measurement error of a diffraction angle on thermal events in DSC is approximately plus or minus 5 °C, and this degree of measurement error must be taken into account when considering the DSC data included here.

[00242] Therefore, in one embodiment, a crystalline form, Form A of 8-[6-(3-dimethylaminopropoxy)pyridin-3-yl]-3-methyl-1-(oxan-4-yl)imidazo is provided [5,4-c]quinolin-2-one which has an endotherm in the DSC with onset of melting at approximately 212.3°C and peaking at approximately 214.1°C.

[00243] Therefore, in one embodiment, a crystalline form, Form A of 8-[6-(3-dimethylaminopropoxy)pyridin-3-yl]-3-methyl-1-(oxan-4-yl)imidazo is provided [5,4-c]quinolin-2-one that has a DSC endotherm with melt onset at 212.3 °C plus or minus 5 °C and peak at 214.1 °C plus or minus 5 °C.

[00244] In one embodiment, a crystalline form, Form A of 8-[6-(3-dimethylaminopropoxy)pyridin-3-yl]-3-methyl-1-(oxan-4-yl)imidazo[5, is provided 4-c]quinolin-2-one which has a DSC endotherm with melt onset at 212.3°C and peak at 214.1°C.

[00245] In one embodiment, a crystalline form, Form A of 8-[6-(3-dimethylaminopropoxy)pyridin-3-yl]-3-methyl-1-(oxan-4-yl)imidazo[5, is provided 4-c]quinolin-2-one which has a DSC thermogram substantially as shown in Figure 2.

[00246] When a modality is stated to refer to a crystalline form, the degree of crystallinity may be greater than about 60%. In some embodiments, the degree of crystallinity is greater than about 80%. In some embodiments, the degree of crystallinity is greater than about 90%. In some embodiments, the degree of crystallinity is greater than approximately 95%. In some embodiments, the degree of crystallinity is greater than approximately 98%.

[00247] The compounds of Formula (I) can, for example, be prepared by reacting a compound of Formula (II):

[00248] Or a salt thereof, wherein Q, R3, R4 and R5 are as defined in any of the described embodiments and X is a leaving group (for example, a halogen atom or, alternatively, a fluorine atom) with a compound of Formula (III):

[00249] Or a salt thereof, wherein R1 and R2 are as defined in any of the described embodiments. The reaction is conveniently carried out in a suitable solvent (e.g. DMF, DMA or THF) and in the presence of a base (e.g. sodium hydride) at a suitable temperature (e.g. a temperature in the range of approximately 20-50 °C).

[00250] The compounds of Formula (II), and their salts, are therefore useful as intermediates in the preparation of compounds of Formula (I) and provide an additional modality.

[00251] In one embodiment, a compound of Formula (II) or its salt is provided, in which:

[00252] Q is a cyclobutyl or cyclopentyl ring, each of which is optionally substituted with a hydroxy or methoxy group, or Q is an oxetanyl, tetrahydrofuranyl or oxanyl ring, each of which is optionally substituted with a methyl group;

[00253] R3 is hydrogen or fluorine;

[00254] R4 is hydrogen or methyl;

[00255] R5 is hydrogen or fluorine; It is

[00256] X is a leaving group. In one embodiment, X is a halogen atom or a triflate group. In one embodiment, X is a fluorine atom.

[00257] In one embodiment, a compound of Formula (II) or its salt is provided, in which:

[00258] Q is cyclobutyl, 1-methoxy-cyclobut-3-yl, 1-hydroxy-cyclobut-3-yl, 3-methoxycyclopent-1-yl, oxetan-3-yl, tetrahydrofuran-3-yl, oxan -3-yl, oxan-4-yl or 4-methylaoxan-4-yl;

[00259] R3 is hydrogen or fluorine;

[00260] R4 is hydrogen or methyl;

[00261] R5 is hydrogen or fluorine; It is

[00262] X is a leaving group. In one embodiment, X is a halogen atom or a triflate group. In one embodiment, X is a fluorine atom.

[00263] In one embodiment, a compound of Formula (II) or its salt is provided, in which:

[00264] Q is 1-methoxy-cyclobut-3-yl, 1-hydroxy-cyclobut-3-yl, 3-methoxycyclopent-1-yl, oxetan-3-yl, oxan-3-yl, oxan-4-yl or 4-methylaoxan-4-yl;

[00265] R3 is hydrogen or fluorine;

[00266] R4 is hydrogen or methyl;

[00267] R5 is hydrogen or fluorine; It is

[00268] X is a leaving group. In one embodiment, X is a halogen atom or a triflate group. In one embodiment, X is a fluorine atom.

[00269] In one embodiment, 8-(6-fluoropyridin-3-yl)-3-methyl-1-(oxan-4-yl)imidazo[5,4-c]quinolin-2-one, or its salt.

[00270] In one embodiment, 8-(6-fluoropyridin-3-yl)-1-(cis-3-methoxycyclobutyl)-3-methylimidazo[4,5-c]quinolin-2-one, or its salt is provided .

[00271] In any of the embodiments in which a compound of Formula (II) or its salt is mentioned, it is to be understood that such salts need not be pharmaceutically acceptable salts. A suitable salt of a compound of Formula (II) is, for example, an acid addition salt. An acid addition salt of a compound of Formula (II) can be formed by bringing the compound into contact with a suitable inorganic or organic acid under conditions known to one skilled in the art. An acid addition salt may, for example, be formed using an inorganic acid selected from the group consisting of hydrochloric acid, hydrobromic acid, sulfuric acid and phosphoric acid. An acid addition salt may also be formed using an organic acid selected from the group consisting of trifluoroacetic acid, citric acid, maleic acid, oxalic acid, acetic acid, formic acid, benzoic acid, fumaric acid, succinic acid, tartaric acid , lactic acid, pyruvic acid, methanesulfonic acid, benzenesulfonic acid and para-toluenesulfonic acid.

[00272] Therefore, in one embodiment, there is provided a compound of Formula (II) or its salt, wherein the salt is a salt of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, trifluoroacetic acid, citric acid, maleic acid , oxalic acid, acetic acid, formic acid, benzoic acid, fumaric acid, succinic acid, tartaric acid, lactic acid, pyruvic acid, methanesulfonic acid, benzenesulfonic acid or para-toluenesulfonic acid.

[00273] The compounds of Formula (II) can, for example, be prepared by reacting a compound of Formula (IV):

[00274] wherein Q, R4 and R5 are as defined in any of the described embodiments, and X1 is a leaving group (e.g. an iodine, bromine or chlorine atom or a triflate group or alternatively a carbon atom bromine) with a compound of Formula (V):

[00275] Or its salt, wherein R3 and X are as defined in any of the described embodiments, where Y is a boronic acid, a boronic ester, or a potassium trifluoroborate group (for example, boronic acid, pinacol acid ester boronic acid or potassium trifluoroborate). The reaction may be carried out under standard conditions well known to the person skilled in the art, for example in the presence of a palladium source (for example palladium tetrakistriphenylphosphine or palladium(II) acetate), optionally a phosphine ligand (for example , Xantphos or S-phos), and a suitable base (e.g. cesium carbonate or triethylamine).

[00276] The compounds of Formula (IV) are therefore useful as intermediates in the preparation of the compounds of Formula (I) and provide an additional modality.

[00277] In one embodiment, a compound of Formula (IV) or its salt is provided, in which:

[00278] Q is a cyclobutyl or cyclopentyl ring, each of which is optionally substituted with a hydroxy or methoxy group, or Q is an oxetanyl, tetrahydrofuranyl or oxanyl ring, each of which is optionally substituted with a methyl group;

[00279] R4 is hydrogen or methyl;

[00280] R5 is hydrogen or fluorine; It is

[00281] X1 is a starting group. In one embodiment, X1 is an iodine, bromine or chlorine atom or a triflate group. In one embodiment, X1 is a bromine atom.

[00282] In one embodiment, a compound of Formula (IV) or its salt is provided, in which:

[00283] Q is cyclobutyl, 1-methoxy-cyclobut-3-yl, 1-hydroxy-cyclobut-3-yl, 3-methoxycyclopent-1-yl, oxetan-3-yl, tetrahydrofuran-3-yl, oxan -3-yl, oxan-4-yl or 4-methyloxan-4-yl;

[00284] R4 is hydrogen or methyl;

[00285] R5 is hydrogen or fluorine; It is

[00286] X1 is a starting group. In one embodiment, X1 is an iodine, bromine or chlorine atom or a triflate group. In one embodiment, X1 is a bromine atom.

[00287] In one embodiment, a compound of Formula (IV) or its salt is provided, in which:

[00288] Q is 1-methoxy-cyclobut-3-yl, 1-hydroxy-cyclobut-3-yl, 3-methoxycyclopent-1-yl, oxetan-3-yl, oxan-3-yl, oxan-4-yl or 4-methyloxan-4-yl;

[00289] R4 is hydrogen or methyl;

[00290] R5 is hydrogen or fluorine; It is

[00291] X1 is a starting group. In one embodiment, X1 is an iodine, bromine or chlorine atom or a triflate group. In one embodiment, X1 is a bromine atom.

[00292] In one embodiment, 8-bromo-3-methyl-1-(oxan-4-yl)imidazo[5,4-c]quinolin-2-one is provided.

[00293] In one embodiment, 8-bromo-1-(cis-3-methoxycyclobutyl)-3-methylimidazo[4,5-c]quinolin-2-one is provided.

[00294] The compounds of Formula (IV) can be prepared by methods similar to those shown in the Examples section.

[00295] The compounds of Formula (I) can also be prepared by reacting a compound of Formula (IV), as described above, with a compound of Formula (VI):

[00296] Wherein R1, R2 and R3 are as defined in any of the described embodiments, where Y is a boronic acid, a boronic ester or a potassium trifluoroborate group (for example, boronic acid, boronic acid pinacol ester or potassium trifluoroborate). The reaction may be carried out under standard conditions well known to those skilled in the art, for example in the presence of a palladium source (e.g. palladium tetrakistriphenylphosphine or palladium(II) acetate), optionally a phosphine ligand (e.g. e.g. Xantphos or S-phos) and a suitable base (e.g. cesium carbonate or triethylamine).

[00297] The compounds of Formula (VI) can be prepared by methods similar to those shown in the Examples section.

[00298] As a result of their ATM kinase inhibitory activity, the compounds of Formula (I), and their pharmaceutically acceptable salts, are expected to be useful in therapy, for example, in the treatment of diseases or medical conditions mediated by least in part by ATM kinase, including cancer.

[00299] When "cancer" is mentioned, both non-metastatic and metastatic cancers are included, such that treating cancer involves treating primary tumors as well as tumor metastases.

[00300] "ATM kinase inhibitory activity" refers to a decrease in ATM kinase activity as a direct or indirect response to the presence of a compound of Formula (I), or its pharmaceutically acceptable salt, in relation to the activity of ATM kinase in the absence of the compound of Formula (I), or its pharmaceutically acceptable salt. Such a decrease in activity may be due to the direct interaction of the compound of Formula (I) or its pharmaceutically acceptable salt with ATM kinase, or due to the interaction of the compound of Formula (I) or its pharmaceutically acceptable salt with one or more other factors which, in turn, affect ATM kinase activity. For example, the compound of Formula (I), or its pharmaceutically acceptable salt, can decrease ATM kinase by binding directly to ATM kinase, causing (directly or indirectly) another factor to decrease ATM kinase activity, or decreasing (directly or indirectly) the amount of ATM kinase present in the cell or organism.

[00301] The term "therapy" is intended to have its normal meaning of dealing with an illness in order to fully or partially alleviate one, some, or all of its symptoms, or to correct or compensate for the underlying pathology. The term "therapy" also includes "prophylaxis" unless there are specific indications to the contrary. The term "therapeutically" and "therapeutically" are to be interpreted accordingly.

[00302] The term "prophylaxis" is intended to have its normal meaning and includes primary prophylaxis, to prevent the development of the disease, and secondary prophylaxis in which the disease has already developed and the patient is temporarily or permanently protected against exacerbation or the worsening of the disease or the development of new symptoms associated with the disease.

[00303] The term "treatment" is used interchangeably with "therapy". Likewise, the term "treat" can be seen as "applying therapy" where "therapy" is as defined above.

[00304] In one embodiment, there is provided a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in therapy.

[00305] In one embodiment, there is provided the use of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, for the production of a medicament.

[00306] In one embodiment, there is provided a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in treating an ATM kinase mediated disease. In one embodiment, said ATM kinase-mediated disease is cancer. In one embodiment, said cancer is selected from the group consisting of colorectal cancer, glioblastoma, gastric cancer, ovarian cancer, diffuse large B-cell lymphoma, chronic lymphocytic leukemia, acute myeloid leukemia, head squamous cell carcinoma and neck cancer, breast cancer, hepatocellular carcinoma, small cell lung cancer and non-small cell lung cancer. In one embodiment, said cancer is selected from the group consisting of colorectal cancer, glioblastoma, gastric cancer, ovarian cancer, diffuse large B-cell lymphoma, chronic lymphocytic leukemia, squamous cell carcinoma of the head and neck, and lung cancer . In one embodiment, said cancer is colorectal cancer.

[00307] In one embodiment, there is provided a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer.

[00308] In one embodiment, there is provided a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in the treatment of Huntington's disease.

[00309] In one embodiment, the use of the compound of Formula (I), or its pharmaceutically acceptable salt, in the manufacture of a medicament for the treatment of an ATM kinase mediated disease is provided. In one embodiment, said ATM kinase mediated disease is cancer. In one embodiment, said cancer is selected from the group consisting of colorectal cancer, glioblastoma, gastric cancer, ovarian cancer, diffuse large B-cell lymphoma, chronic lymphocytic leukemia, acute myeloid leukemia, squamous cell carcinoma of the head and neck , breast cancer, hepatocellular carcinoma, small cell lung cancer and non-small cell lung cancer. In one embodiment, said cancer is selected from the group consisting of colorectal cancer, glioblastoma, gastric cancer, ovarian cancer, diffuse large B-cell lymphoma, chronic lymphocytic leukemia, squamous cell carcinoma of the head and neck, and lung cancer . In one embodiment, said cancer is colorectal cancer.

[00310] In one embodiment, the use of the compound of Formula (I), or its pharmaceutically acceptable salt, in the manufacture of a medicament for the treatment of cancer is provided.

[00311] In one embodiment, there is provided a method of treating a disease in which ATM kinase inhibition is beneficial in a warm-blooded animal in need of such treatment, which comprises administering to said warm-blooded animal a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof. In one embodiment, said disease is cancer. In one embodiment, said cancer is selected from the group consisting of colorectal cancer, glioblastoma, gastric cancer, ovarian cancer, diffuse large B-cell lymphoma, chronic lymphocytic leukemia, acute myeloid leukemia, squamous cell carcinoma of the head and neck , breast cancer, hepatocellular carcinoma, small cell lung cancer and non-small cell lung cancer. In one embodiment, said cancer is selected from the group consisting of colorectal cancer, glioblastoma, gastric cancer, ovarian cancer, diffuse large B-cell lymphoma, chronic lymphocytic leukemia, squamous cell carcinoma of the head and neck, and lung cancer . In one embodiment, said cancer is colorectal cancer.

[00312] The term "therapeutically effective amount" refers to an amount of a compound of Formula (I), as described in either embodiment, that is effective to provide "therapy" in an individual, or to "treat" a disease or disorder in an individual. In the case of cancer, the therapeutically effective amount may elicit any of the observable or measurable changes in an individual as described in the definition of "therapy", "treatment", and "prophylaxis" above. For example, the effective amount can reduce the number of cancerous or tumor cells; reduce the overall size of the tumor; inhibit or stop tumor cell infiltration into peripheral organs, including, for example, soft tissue and bone; inhibit and stop tumor metastases; inhibit and stop tumor growth; relieve to some extent one or more of the symptoms associated with the cancer; reduce morbidity and mortality; improve the life quality; or a combination of such effects. An effective amount can be that amount sufficient to lessen the symptoms of a responding disease, and in vivo efficacy can, for example, be measured by assessing duration of survival, time to disease progression (TTP), response rates (RR), duration of response and/or quality of life. As recognized by those skilled in the art, effective amounts may vary depending on route of administration, use of excipients, and concomitant use with other agents. For example, when a combination therapy is used, the amount of the compound of Formula (I) or its pharmaceutically acceptable salt described in this specification and the amount of other pharmaceutically active agent(s) (s) are, when combined, jointly efficacious to treat a targeted disorder in the animal patient. In this context, the combined amounts are a "therapeutically effective amount" if they are, when combined, sufficient to lessen the symptoms of a disease that responds to inhibition of TMJ activity as described above. Typically, such amounts can be determined by those skilled in the art, for example, starting with the dose range described in this specification for the compound of Formula (I), or its pharmaceutically acceptable salt, and an approved dose range or the otherwise published of the other pharmaceutically active compound(s).

[00313] "Warm-blooded animals" include, for example, humans.

[00314] In one embodiment, there is provided a method of treating cancer in a warm-blooded animal in need of such treatment, which comprises administering to said warm-blooded animal a therapeutically effective amount of a compound of Formula (I), or of its pharmaceutically acceptable salt. In one embodiment, said cancer is selected from the group consisting of colorectal cancer, glioblastoma, gastric cancer, ovarian cancer, diffuse large B-cell lymphoma, chronic lymphocytic leukemia, acute myeloid leukemia, head squamous cell carcinoma and neck cancer, breast cancer, hepatocellular carcinoma, small cell lung cancer and non-small cell lung cancer. In one embodiment, said cancer is selected from the group consisting of colorectal cancer, glioblastoma, gastric cancer, ovarian cancer, diffuse large B-cell lymphoma, chronic lymphocytic leukemia, squamous cell carcinoma of the head and neck, and cancer. lung. In one embodiment, said cancer is colorectal cancer.

[00315] In any embodiment where cancer is mentioned in a general sense, said cancer may be selected from the group consisting of colorectal cancer, glioblastoma, gastric cancer, ovarian cancer, diffuse large B-cell lymphoma, chronic lymphocytic leukemia, acute myeloid leukemia, squamous cell carcinoma of the head and neck, breast cancer, hepatocellular carcinoma, small cell lung cancer, and non-small cell lung cancer. Said cancer can also be selected from the group consisting of colorectal cancer, glioblastoma, gastric cancer, ovarian cancer, diffuse large B-cell lymphoma, chronic lymphocytic leukemia, squamous cell carcinoma of the head and neck and lung cancer. .

[00316] In any modality where cancer is mentioned in a general sense, the following modalities may apply:

[00317] In one embodiment, the cancer is colorectal cancer.

[00318] In one embodiment, the cancer is glioblastoma.

[00319] In one embodiment, the cancer is gastric cancer.

[00320] In one embodiment, the cancer is esophageal cancer.

[00321] In one embodiment, the cancer is ovarian cancer.

[00322] In one embodiment, the cancer is endometrial cancer.

[00323] In one embodiment, the cancer is cervical cancer.

[00324] In one embodiment, the cancer is diffuse large B-cell lymphoma.

[00325] In one embodiment, the cancer is chronic lymphocytic leukemia.

[00326] In one embodiment, the cancer is acute myeloid leukemia.

[00327] In one embodiment, the cancer is squamous cell carcinoma of the head and neck.

[00328] In one embodiment, the cancer is breast cancer. In one embodiment, the cancer is triple negative breast cancer.

[00329] "Triple negative breast cancer" is any breast cancer that does not express the genes for the estrogen receptor, the progesterone receptor, and Her2/neu.

[00330] In one embodiment, the cancer is hepatocellular carcinoma.

[00331] In one embodiment, the cancer is lung cancer. In one embodiment, the lung cancer is small cell lung cancer. In one embodiment, the lung cancer is non-small cell lung cancer.

[00332] In one embodiment, the cancer is metastatic cancer. In one embodiment, metastatic cancer comprises central nervous system metastases. In one embodiment, the central nervous system metastases comprise brain metastases. In one embodiment, the central nervous system metastases comprise leptomeningeal metastases.

[00333] "Leptomeningeal metastases" occur when cancer spreads to the meninges, the layers of tissue that cover the brain and spinal cord. Metastases may spread to the meninges through the blood or they may travel from brain metastases, carried by the cerebrospinal fluid (CSF) flowing through the meninges. In one embodiment, the cancer is non-metastatic cancer. The cancer treatment described in this specification may be useful as a stand-alone therapy, or may involve, in addition to the administration of the compound of Formula (I), surgery, radiotherapy or conventional chemotherapy; or a combination of such additional therapies. Such surgery, radiotherapy or conventional chemotherapy may be administered concurrently, sequentially or separately from treatment with the compound of Formula (I).

[00334] Radiotherapy may include one or more of the following categories of therapy:

[00335] i. External radiation therapy using electromagnetic radiation and intraoperative radiation therapy using electromagnetic radiation;

[00336] ii. Internal radiation therapy or brachytherapy; including interstitial radiation therapy or intraluminal radiation therapy; or

[00337] iii. Systemic radiation therapy, including but not limited to iodine 131 and strontium 89.

[00338] Accordingly, in one embodiment, there is provided a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and radiotherapy, for use in the treatment of cancer. In one embodiment, the cancer is glioblastoma. In one embodiment, the cancer is metastatic cancer. In one embodiment, metastatic cancer comprises metastases of the central nervous system. In one embodiment, the central nervous system metastases comprise brain metastases. In one embodiment, the central nervous system metastases comprise leptomeningeal metastases.

[00339] In one embodiment, a compound of Formula (I) or a pharmaceutically acceptable salt thereof is provided for use in the treatment of cancer, wherein the compound of Formula (I) or a pharmaceutically acceptable salt thereof is administered in combination with radiotherapy. In one embodiment, the cancer is glioblastoma. In one embodiment, the cancer is metastatic cancer. In one embodiment, metastatic cancer comprises central nervous system metastases. In one embodiment, the central nervous system metastases comprise brain metastases. In one embodiment, the central nervous system metastases comprise leptomeningeal metastases.

[00340] In one embodiment, there is provided a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and radiotherapy, for use in the simultaneous, separate or sequential treatment of cancer. In one embodiment, the cancer is selected from glioblastoma, lung cancer (e.g., small cell lung cancer or non-small cell lung cancer), breast cancer (e.g., triple negative breast cancer), head and neck squamous cell carcinoma, esophageal cancer, cervical cancer and endometrial cancer. In one embodiment, the cancer is glioblastoma. In one embodiment, the cancer is metastatic cancer. In one embodiment, metastatic cancer comprises central nervous system metastases. In one embodiment, the central nervous system metastases comprise brain metastases. In one embodiment, the central nervous system metastases comprise leptomeningeal metastases.

[00341] In one embodiment, a compound of Formula (I) or a pharmaceutically acceptable salt thereof is provided for use in the treatment of cancer, wherein the compound of Formula (I) or a pharmaceutically acceptable salt thereof is administered simultaneously, separately or sequentially with radiotherapy. In one embodiment, the cancer is selected from glioblastoma, lung cancer (e.g., small cell lung cancer or non-small cell lung cancer), breast cancer (e.g., triple negative breast cancer), head and neck squamous cell carcinoma, esophageal cancer, cervical cancer and endometrial cancer. In one embodiment, the cancer is glioblastoma. In one embodiment, the cancer is metastatic cancer. In one embodiment, metastatic cancer comprises central nervous system metastases. In one embodiment, central nervous system metastases comprise brain metastases. In one embodiment, the central nervous system metastases comprise leptomeningeal metastases.

[00342] In one embodiment, there is provided a method of treating cancer in a warm-blooded animal in need of such treatment, which comprises administering to said warm-blooded animal a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and radiotherapy, wherein the compound of Formula (I), or its pharmaceutically acceptable salt, and radiotherapy are jointly effective in producing an anti-cancer effect. In one embodiment, the cancer is selected from glioblastoma, lung cancer (e.g., small cell lung cancer or non-small cell lung cancer), breast cancer (e.g., triple negative breast cancer), head and neck squamous cell carcinoma, esophageal cancer, cervical cancer and endometrial cancer. In one embodiment, the cancer is glioblastoma. In one embodiment, the cancer is metastatic cancer. In one embodiment, metastatic cancer comprises central nervous system metastases. In one embodiment, the central nervous system metastases comprise brain metastases. In one embodiment, the central nervous system metastases comprise leptomeningeal metastases.

[00343] In one embodiment, a method is provided for treating cancer in a warm-blooded animal in need of such treatment, which comprises administering to said warm-blooded animal a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and administering radiotherapy simultaneously, separately or sequentially, wherein the compound of Formula (I), or a pharmaceutically acceptable salt thereof, and the radiotherapy are jointly effective in producing an anti-cancer effect. In one embodiment, the cancer is glioblastoma. In one embodiment, the cancer is metastatic cancer. In one embodiment, metastatic cancer comprises central nervous system metastases. In one embodiment, the central nervous system metastases comprise brain metastases. In one embodiment, the central nervous system metastases comprise leptomeningeal metastases.

[00344] In any modality, radiotherapy is selected from the group consisting of one or more of the categories of radiotherapy listed under points (i) - (iii) above.

[00345] Chemotherapy may include one or more of the following categories of antitumor substance:

[00346] i. Antineoplastic agents and combinations thereof, such as DNA alkylating agents (eg, cisplatin, oxaliplatin, carboplatin, cyclophosphamide, nitrogen mustards such as ifosfamide, bendamustine, melphalan, chlorambucil, busulfan, temozolamide, and nitrosoureas such as carmustine); antimetabolites (eg gemcitabine and antifolates such as fluoropyrimidines such as 5-fluorouracil and tegafur, raltitrexed, methotrexate, cytosine arabinoside and hydroxyurea); antitumor antibiotics (eg, anthracyclines such as adriamycin, bleomycin, doxorubicin, liposomal doxorubicin, pyrarubicin, daunomycin, valrubicin, epirubicin, idarubicin, mitomycin-C, dactinomycin, anrubicin, and mithramycin); antimitotic agents (for example vinca alkaloids like vincristine, vinblastine, vindesine and vinorelbine and taxoids like taxol and taxotere and polokinase inhibitors); and topoisomerase inhibitors (for example, epipodophyllotoxins such as etoposide and teniposide, ansacrine, irinotecan, topotecan and camptothecin); inhibitors of DNA repair mechanisms such as CHK kinase; DNA-dependent protein kinase inhibitors; poly(ADP-ribose) polymerase inhibitors (PARP inhibitors, including olaparib); and Hsp90 inhibitors such as tanespimycin and retaspimycin, ATR kinase inhibitors (such as AZD6738); and WEE1 kinase inhibitors (such as AZD1775/MK-1775);

[00347] ii. Antiangiogenic agents such as those that inhibit the effects of vascular endothelial growth factor, e.g. the anti-vascular endothelial growth factor antibody bevacizumbe, and e.g. a VEGF receptor tyrosine kinase inhibitor such as vandetanib (ZD6474), sorafenib, vatalanib ( PTK787), sunitinib (SU11248), axitinib (AG-013736), pazopanib (GW 786034) and cediranib (AZD2171); compounds such as those described in International Patent Applications WO97/22596, WO 97/30035, WO 97/32856 and WO 98/13354; and compounds that operate by other mechanisms (for example, linomide, inhibitors of αvβ3 integrin function and angiostatin), or inhibitors of angiopoietins and their receptors (Tie-1 and Tie-2), PLGF inhibitors, delta ligand inhibitors -like (DLL-4);

[00348] iii. Immunotherapeutic approaches, including, for example, ex vivo and in vivo approaches to enhance the immunogenicity of the patient's tumor cells, such as transfection with cytokines such as interleukin 2, interleukin 4, or granulocyte-macrophage colony-stimulating factor; approaches to decreasing T cell anergy or T cell function; approaches that enhance T-cell responses against tumors, such as blocking antibodies against CTLA4 (e.g., ipilimumab and tremelimumab), B7H1, PD-1 (e.g., BMS-936558 or AMP-514), PD-L1 (e.g., MEDI4736) and agonist antibodies against CD137; approaches using transfected immune cells, such as cytokine-transfected dendritic cells; approaches using cytokine-transfected tumor cell lines, approaches using antibodies against tumor-associated antigens, and antibodies that deplete target cell types (eg, unconjugated anti-CD20 antibodies such as Rituximab, radiolabeled anti-CD20 antibodies). -CD20 like Bexxar and Zevalin, and anti-CD54 antibody like Campath); approaches using anti-idiotypic antibodies; approaches that enhance Natural Killer cell function; and approaches using antibody-toxin conjugates (e.g., the anti-CD33 antibody Mylotarg); immunotoxins such as moxetumumab pasudotox; toll-like receptor 7 or toll-like receptor 9 agonists;

[00349] iv. Efficacy enhancers such as leucovorin.

[00350] Accordingly, in one embodiment, there is provided a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and at least one additional antitumor substance, for use in the treatment of cancer. In one embodiment, there is provided a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer, wherein the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered in combination with a additional antitumor substance. In one embodiment, it is an additional antitumor substance. In one embodiment, it is two additional antitumor substances. In one embodiment, it is three or more additional antitumor substances.

[00351] In one embodiment, there is provided a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and at least one additional antitumor substance for use in the simultaneous, separate or sequential treatment of cancer. In one embodiment, there is provided a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer, wherein the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered concurrently, separately or sequentially with an additional antitumor substance.

[00352] In one embodiment, there is provided a method of treating cancer in a warm-blooded animal in need of such treatment, which comprises administering to said warm-blooded animal a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and at least one additional antitumor substance, wherein the amounts of the compound of Formula (I), or its pharmaceutically acceptable salt, and the additional antitumor substance are jointly effective in producing an anticancer effect.

[00353] In one embodiment, a method is provided for treating cancer in a warm-blooded animal in need of such treatment, which comprises administering to said warm-blooded animal a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and simultaneously, separately or sequentially administering at least one additional antitumor substance to said warm-blooded animal, wherein the amounts of the compound of Formula (I), or its pharmaceutically acceptable salt, and the additional antitumor substance are jointly effective in producing an effect against cancer.

[00354] In either embodiment, the additional antitumor substance is selected from the group consisting of one or more of the antitumor substances listed under points (i) - (iv) above.

[00355] In one embodiment, there is provided a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and at least one antineoplastic agent for use in the treatment of cancer. In one embodiment, there is provided a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer, wherein the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered in combination with at least one antineoplastic agent. In one embodiment, the antineoplastic agent is selected from the list of antineoplastic agents in point (i) above.

[00356] In one embodiment, there is provided a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and at least one antineoplastic agent for use in the simultaneous, separate or sequential treatment of cancer. In one embodiment, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, is provided for use in the treatment of cancer, wherein the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered concurrently. , separate or sequential with at least one antineoplastic agent. In one embodiment, the antineoplastic agent is selected from the list of antineoplastic agents in point (i) above.

[00357] In one embodiment, a compound of Formula (I), or its pharmaceutically acceptable salt, and at least one additional antitumor substance selected from the group consisting of cisplatin, oxaliplatin, carboplatin, valrubicin, idarubicin, doxorubicin is provided , pyrarubicin, irinotecan, topotecan, anrubicin, epirubicin, etoposide, mitomycin, bendamustine, chlorambucil, cyclophosphamide, ifosfamide, carmustine, melphalan, bleomycin, olaparib, ME-DI4736, AZD1775 and AZD6738, for use in the treatment of cancer.

[00358] In one embodiment, there is provided a compound of Formula (I), or its pharmaceutically acceptable salt, and at least one additional antitumor substance selected from the group consisting of cisplatin, oxaliplatin, carboplatin, doxorubicin, pyrarubicin, irinotecan, topotecan , anrubicin, epirubicin, etoposide, mitomycin, bendamustine, chlorambucil, cyclophosphamide, ifosfamide, carmustine, melphalan, bleomycin, olaparib, AZD1775 and AZD6738, for use in the treatment of cancer.

[00359] In one embodiment, a compound of Formula (I) or a pharmaceutically acceptable salt thereof is provided for use in the treatment of cancer, wherein the compound of Formula (I) or a pharmaceutically acceptable salt thereof is administered in combination with at least one additional antitumor substance selected from the group consisting of cisplatin, oxaliplatin, carboplatin, valrubicin, idarubicin, doxorubicin, pyrarubicin, irinotecan, topotecan, anrubicin, epirubicin, etoposide, mitomycin, bendamustine, chlorambucil, cyclophosph famide, ifosfamide, carmustine, melphalan, bleomycin, olaparib, ME-DI4736, AZD1775 and AZD6738.

[00360] In one embodiment, there is provided a compound of Formula (I), or its pharmaceutically acceptable salt, and at least one additional antitumor substance selected from the group consisting of doxorubicin, irinotecan, topotecan, etoposide, mitomycin, bendamustine, chlorambucil , cyclophosphamide, ifosfamide, carmustine, melphalan, bleomycin and olaparib for use in the treatment of cancer.

[00361] In one embodiment, a compound of Formula (I) or a pharmaceutically acceptable salt thereof is provided for use in the treatment of cancer, wherein the compound of Formula (I) or a pharmaceutically acceptable salt thereof is administered in combination with at least one additional antitumor substance selected from the group consisting of doxorubicin, irinotecan, topotecan, etoposide, mitomycin, bendamustine, chlorambucil, cyclophosphamide, ifosfamide, carmustine, melphalan, bleomycin and olaparib.

[00362] In one embodiment, there is provided a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and at least one additional antitumor substance selected from the group consisting of doxorubicin, irinotecan, topotecan, etoposide, mitomycin, bendamustine, chlorambucil , cyclophosphamide, ifosfamide, carmustine, melphalan and bleomycin, for use in the treatment of cancer.

[00363] In one embodiment, a compound of Formula (I) or a pharmaceutically acceptable salt thereof is provided for use in the treatment of cancer, wherein the compound of Formula (I) or a pharmaceutically acceptable salt thereof is administered in combination with at least one additional antitumor substance selected from the group consisting of doxorubicin, irinotecan, topotecan, etoposide, mitomycin, bendamustine, chlorambucil, cyclophosphamide, ifosfamide, carmustine, melphalan and bleomycin.

[00364] In one embodiment, a compound of Formula (I) or a pharmaceutically acceptable salt thereof is provided for use in the treatment of cancer, wherein the compound of Formula (I) or a pharmaceutically acceptable salt thereof is administered in combination with at least one additional antitumor substance selected from the group consisting of doxorubicin, pyrarubicin, anrubicin and epirubicin. In one embodiment, the cancer is acute myeloid leukemia. In one embodiment, the cancer is breast cancer (e.g., triple negative breast cancer). In one embodiment, the cancer is hepatocellular carcinoma.

[00365] In one embodiment, there is provided a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and irinotecan, for use in treating cancer. In one embodiment, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, is provided for use in the treatment of cancer, wherein the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered in combination with irino-tecan. In one embodiment, the cancer is colorectal cancer.

[00366] In one embodiment, there is provided a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and FOLFIRI, for use in treating cancer. In one embodiment, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, is provided for use in the treatment of cancer, wherein the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered in combination with FOL-FIRI. In one embodiment, the cancer is colorectal cancer.

[00367] FOLFIRI is a dosing regimen involving a combination of leucovorin, 5-fluorouracil, and irinotecan.

[00368] In one embodiment, a compound of Formula (I) or a pharmaceutically acceptable salt thereof is provided for use in the treatment of cancer, wherein the compound of Formula (I) or a pharmaceutically acceptable salt thereof is administered in combination with olaparib. In one embodiment, the cancer is gastric cancer.

[00369] In one embodiment, a compound of Formula (I) or a pharmaceutically acceptable salt thereof is provided for use in treating cancer, wherein the compound of Formula (I) or a pharmaceutically acceptable salt thereof is administered in combination with topotecan. In one embodiment, the cancer is small cell lung cancer. In one embodiment, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, is provided for use in the treatment of cancer, wherein the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered in combination with immunotherapy. In one embodiment, the immunotherapy is one or more of the agents listed under point (iii) above. In one embodiment, the immunotherapy is an anti-PD-L1 antibody (eg, MEDI4736).

[00370] In one embodiment, a pharmaceutical composition comprising a compound of Formula (I) and at least one additional antitumor substance is provided. In one embodiment, the pharmaceutical composition also comprises at least one pharmaceutically acceptable diluent or carrier. In one embodiment, the antitumor substance is an antineoplastic agent.

[00371] In one embodiment, there is provided a pharmaceutical composition comprising a compound of Formula (I) and at least one additional antitumor substance, for use in the treatment of cancer. In one embodiment, the pharmaceutical composition also comprises at least one pharmaceutically acceptable diluent or carrier. In one embodiment, the antitumor substance is an antineoplastic agent.

[00372] According to an additional embodiment, a kit comprising:

[00373] a) A compound of Formula (I), or a pharmaceutically acceptable salt thereof, in a first unit dose form;

[00374] b) An additional additional antitumor substance in an additional unit dose form;

[00375] c) A container as a means for containing said first and additional unit dose forms; and optionally

[00376] d) Instructions for use. In one embodiment, the antitumor substance comprises an antineoplastic agent.

[00377] In any embodiment in which an antineoplastic agent is mentioned, the antineoplastic agent is one or more of the agents listed under point (i) above.

[00378] The compounds of Formula (I), and their pharmaceutically acceptable salts, can be administered as pharmaceutical compositions including one or more pharmaceutically acceptable diluents or carriers.

[00379] Accordingly, in one embodiment, there is provided a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable diluent or carrier.

[00380] The compositions may be in a form suitable for oral use (for example, as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), for topical use (for for example, as creams, ointments, gels or aqueous or oily solutions or suspensions), for administration by inhalation (for example, as a finely divided powder or a liquid aerosol), for administration by insufflation (for example, as a finely divided powder) or for parenteral administration (for example, as a sterile aqueous or oily solution for intravenous, subcutaneous or intramuscular administration) or as a suppository for rectal administration. The compositions can be obtained by conventional procedures using conventional pharmaceutical excipients well known in the art. Thus, compositions intended for oral use may contain, for example, one or more coloring, sweetening, flavoring and/or preservative agents.

[00381] In one embodiment, there is provided a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable diluent or carrier, for use in therapy.

[00382] In one embodiment, there is provided a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable diluent or carrier, for use in the treatment of cancer. In one embodiment, said cancer is selected from the group consisting of colorectal cancer, glioblastoma, gastric cancer, ovarian cancer, diffuse large B-cell lymphoma, chronic lymphocytic leukemia, acute myeloid leukemia, squamous cell carcinoma of the head and neck , breast cancer, hepatocellular carcinoma, small cell lung cancer and non-small cell lung cancer. In one embodiment, said cancer is selected from the group consisting of colorectal cancer, glioblastoma, gastric cancer, ovarian cancer, diffuse large B-cell lymphoma, chronic lymphocytic leukemia, squamous cell carcinoma of the head and neck, and cancer. lung. In one embodiment, said cancer is colorectal cancer.

[00383] The compound of Formula (I) will normally be administered to a warm-blooded animal at a unit dose within the range of 2.5-5000 mg/m2 of the animal's body area or approximately 0.05-100 mg/kg , and this amount normally provides a therapeutically effective dose. A unit dose form such as a tablet or capsule will usually contain, for example, 0.1-250 mg of active ingredient. The daily dose will necessarily vary depending on the host treated, the particular route of administration, any co-administered therapies and the severity of the disease being treated. In this way, the clinician treating any particular patient can determine the optimal dose.

EXAMPLES

[00384] The various embodiments are illustrated by the Examples below. It should not be construed that the invention is limited to the Examples. When preparing the Examples, in general:

[00385] i. Operations were conducted at ambient temperature, i.e. in the range between 17 °C and 30 °C and under atmospheric conditions unless otherwise stated;

[00386] ii. Evaporations were performed by rotary evaporation or using Genevac vacuum equipment, and routine laboratory procedures were performed after removing residual solids by filtration;

[00387] iii. Purifications by ultra-fast chromatography were carried out on an automatic Armen Glider Flash: Spot II Ultimate equipment (Armen Instrument, Saint-Ave, France) or automatic partners Presearch combiflash using pre-packed normal phase Si60 silica cartridges from Merck (granulometry: 15- 40 or 40-63 μm) obtained from Merck, Darmstad, Germany, silicycle silica cartridges or graceresolv silica cartridges;

[00388] iv. Preparative chromatography was performed on a Waters instrument (600/2700 or 2525) equipped with ZMD or ZQ ESCi mass spectrometers and a Waters X-Terra, Waters X-Bridge, or Waters SunFire reverse-phase (C-18, 5-mm silica) column. micron, 19 mm or 50 mm diameter, 100 mm length, flow rate 40 mL/minute) using mixtures of water of decreasing polarity (containing 1% ammonia) and acetonitrile or mixtures of water of decreasing polarity (containing 0.0 formic acid, 1%) and acetonitrile as eluents. Examples 2, 6-8, 13, 16, 18, 19-22, 27, 29, 34, 39, 59, 60, 70 and 71 were isolated directly from preparative HPLC solutions containing formic acid. The isolated material, therefore, comprises a certain amount of formic acid;

[00389] v. Yields, when present, are not necessarily the maximum attainable;

[00390] vi. The structures of final products of Formula (I) were confirmed using nuclear magnetic resonance (NMR) spectroscopy, with NMR chemical shift values measured on the delta scale. Proton magnetic resonance spectra were determined using a Bruker Advance 700 (700 MHz), Bruker Avance 500 (500 MHz), Bruker 400 (400 MHz) or Bruker 300 (300 MHz) instrument; 19F NMR were determined at 282 MHz or 376 MHz; 13C NMR were determined at 75 MHz or 100 MHz; measurements were taken at around 20 - 30 °C unless otherwise specified; the following abbreviations were used: s = singlet; d = doublet; t = triplet; q = quartet; p = pentet/quintet; m = multiplet; dd = doublet of doublets; ddd = doublet doublet doublet; dt = doublet of triplets; td = triplet of doublets; qd = quartet of doublets; bs = wide signal;

[00391] vii. The final products of Formula (I) were further characterized by liquid chromatography mass spectroscopy (LCMS); LCMS was performed using a Waters Alliance HT (2790 and 2795) equipped with a Waters ZQ ESCi or ZMD ESCi mass spectrometer and C-18 X Bridge 5 µm column (2.1 x 50 mm) at a flow rate of 2.4 mL/ minute using a solvent system from A 95% + C 5% to B 95% + C 5% over 4 minutes, where A = water, B = methanol, C = 1:1 methanol:water (containing carbonate ammonium 0.2%); or using a Shimadzu UFLC or UHPLC coupled DAD detector, ELSD detector and 2020 EV mass spectrometer (or equivalent) fitted with a Phenomenex Gemini-NX C18 3.0 x 50 mm, 3.0 μm column or equivalent (basic conditions) , or a Shim pack XR - ODS 3.0 x 50 mm, 2.2 µm column or Waters BEH C18 2.1 x 50 mm, 1.7 µm column or equivalent, using a solvent system of 95% D + E 5% to E 95% + D 5% over 4 minutes, where D = water (containing 0.05% TFA), E = Acetonitrile (containing 0.05% TFA) (acidic conditions) or a solvent system of F 90% + G 10% to G 95% + F 5% over 4 minutes, where F = water (containing 6.5 mM ammonium hydrogen carbonate and pH adjusted to 10 by addition of ammonia), G = Acetonitrile (conditions basic);

[00392] viii. Intermediates were generally not fully characterized, and purity was assessed by thin layer chromatography, mass spectral, HPLC, and/or NMR analysis;

[00393] ix. Powder X-ray diffraction spectra were determined (using a Bruker D4 Analytical Instrument) by creating a sample of the crystalline material on a Bruker single crystal silicon (SSC) wafer mount and spreading the sample into a thin layer with the aid of of a microscope slide. The sample was rotated at 30 revolutions per minute (to improve the counting statistics) and irradiated with X-rays generated by a copper tube with a long fine focus operated at 40 kV and 40 mA with a wavelength of 1.5418 angstroms. The collimated X-ray source was passed through a slit with variable divergence set to V20, and the reflected radiation directed through a 5.89 mm antiscattering slit and a 9.55 mm detector slit. The sample was exposed for 0.03 seconds in 0.00570° 2-theta increments (continuous scan mode) over the range of 2 degrees to 40 degrees 2-theta in theta-theta mode. The running time was 3 minutes and 36 seconds. The instrument was equipped with a position sensitive detector (Lynxeye). Data control and capture was performed using a Dell Optiplex 686 NT 4.0 Workstation operating with Diffrac+ software;

[00394] x. Differential scanning calorimetry was performed on a TA Instruments Q1000 DSC. Typically, less than 5 mg of material contained in a standard aluminum pan fitted with a lid was heated in the temperature range of 25°C to 300°C at a constant heating rate of 10°C per minute. A nitrogen purge gas was used at a flow rate of 50 ml per minute.

[00395] xi. The following abbreviations were used: h = hour(s); r.t. = ambient temperature (~17-30 °C); conc. = concentrated; FCC = ultrafast column chromatography using silica; DCM = dichloromethane; DIPEA = diisopropylethylamine; DMA = N,N-dimethylacetamide; DMF = N,N-dimethylformamide; DMSO = dimethylsulfoxide; Et2O = diethyl ether; EtOAc = ethyl acetate; EtOH = ethanol; K2CO3 = potassium carbonate; MeOH = methanol; MeCN = acetonitrile; MTBE = methyl tert-butyl ether; MgSO4 = anhydrous magnesium sulfate; Na2SO4 = anhydrous sodium sulfate; THF = tetrahydrofuran; sat. = saturated aqueous solution; It is

[00396] xii. IUPAC names were generated using "SmiToSd", a proprietary program built around the OpenEye Lexichem toolkit (http://www.eyesopen.com/lexichem-tk), or Canvas, a different proprietary program. "SmiToSd" was used to name Examples 1 to 22 and 25 to 42, and Canvas to name Examples 23, 24 and 43 to 71. "SmiToSd" did not automatically recognize the stereochemistry of the 3-substituted cyclobut-1-yl group present in some of the Examples, so the names of these Examples have been hand-edited to include the correct stereochemistry of cyclobutyl. Furthermore, as stated in the introduction, the compounds comprise an imidazo[4,5-c]quinolin-2-one nucleus. However, in some Examples, the IUPAC name describes the core as imidazo[5,4-c]quinolin-2-one. The imidazo[4,5-c]quinolin-2-one and imidazo[5,4-c]quinolin-2-one nuclei are nevertheless the same, with the naming convention slightly different because of the peripheral groups. 1 8-[6-(3-dimethylaminopropoxy)pyridin-3-yl]-3-methyl-1-(oxan-4-yl)imidazo[5,4-c]quinolin-2-one

[00397] Sodium hydride (60% dispersion in mineral oil) (21.14 g, 528.56 mmol) was added portionwise to 3-(dimethylamino)propan-1-ol (27.3 g, 264.27 mmol) in DMF (500 mL) at 10 °C over a period of 20 minutes under nitrogen. The resulting mixture was stirred at room temperature for 1 hour. 8-(6-Fluoropyridin-3-yl)-3-methyl-1-(oxan-4-yl)imidazo[5,4-c]quinolin-2-one (50.0 g, 132.14 mmol) was added in portions to the reaction mixture at 10 °C over a period of 20 minutes under nitrogen. The resulting mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with water and the precipitate collected by filtration, washed with water (300 ml) and dried under vacuum. The dried solid was triturated with EtOAc (2 L) and filtered. The crude product was purified by crystallization from MeCN to provide the desired product (50.0 g, 82%) as a white solid. NMR spectrum: 1H NMR (400 MHz, CDCl3) δ 1.90-2.04 (4H, m), 2.29 (6H, s), 2.49 (2H, t), 2.93-3, 07 (2H, m), 3.56-3.67 (5H, m), 4.10-4.30 (2H, m), 4.43 (2H, t), 5.10 (1H, t) , 6.89 (1H, d), 7.80 (1H, d), 7.92 (1H, dd), 8.21 (1H, d), 8.40 (1H, s), 8.51 ( 1H, d), 8.71 (1H, s). Mass spectrum: m/z (ES+)[M+H]+ = 462.3.

[00398] The title material (49.5 g, 107.25 mmol) was suspended in MeCN (300 mL), giving a thick, freely stirring solution. This solution was allowed to stir at room temperature overnight, resulting in a thinner solution. The material was filtered, washed with cold (0 °C) MeCN (200 mL) and dried overnight under vacuum at 30 °C to afford the title material in crystalline form A (48 g, 97%) as a white solid . NMR spectrum: 1H NMR (400 MHz, DMSO-d6) δ 1.81 - 1.99 (4H, m), 2.16 (6H, s), 2.37 (2H, t), 2.73 ( 2H, qd), 3.51 (3H, s), 3.59 (2H, t), 4.07 (2H, dd), 4.37 (2H, t), 5.14 (1H, ddd), 6.94 - 7.01 (1H, m), 7.95 (1H, dd), 8.14 (1H, d), 8.18 (1H, dd), 8.43 (1H, s), 8 .66 (1H, d), 8.89 (1H, s). Mass spectrum: m/z (ES+)[M+H]+ = 462.6.

[00399] The slurry filtrate and washings were combined and evaporated to recover additional title material (580 mg, 1.172%) as a light cream colored solid. The material obtained by the above procedure was determined to be crystalline Form A, which was analyzed by XRPD and provided an X-ray diffraction pattern with the following characteristic peaks.Table 1: Characteristic peaks in powder X-ray diffraction for Form A from 8-[6-(3-dimethylaminopropoxy)pyridin-3-yl]-3-methyl-1-(oxan-4-yl)imidazo[5,4-c]quinolin-2-one

[00400] 8-(6-Fluoropyridin-3-yl)-3-methyl-1-(oxan-4-yl)imidazo[5,4-c]quinolin-2-one can be prepared according to the following procedure .Intermediate A1:8-(6-Fluoropyridin-3-yl)-3-methyl-1-(oxan-4-yl)imidazo[5,4-c]quinolin-2-one

[00401] Disodium monopalladium (IV) tetrachloride (0.975 g, 3.31 mmol) was added to 8-bromo-3-methyl-1-(oxan-4-yl)imidazo[5,4-c]quinolin-2 -one (60.0 g, 165.64 mmol), (6-fluoropyridin-3-yl)boronic acid (25.7 g, 182.21 mmol), K2CO3 (68.7 g, 496.93 mmol) and 3-(di-tert-butylphosphino)propane-1-sulfonic acid (0.445 g, 1.66 mmol) in 1,4-dioxane (400 mL) and water (100 mL) at room temperature under air flow. The resulting mixture was stirred at 80°C for 16 hours. The reaction mixture was diluted with water and the precipitate collected by filtration, washed with water (200 ml) and dried under vacuum. The resulting solid was dissolved with DCM (18 L) and the mixture filtered through celite to remove palladium residue. The solvent was removed under reduced pressure to provide the desired material (60.0 g, 96%) as a white solid, which was used without further purification. NMR spectrum: 1H NMR (400 MHz, CDCl3) δ 1.85-2.01 (2H, m), 2.86-3.02 (2H, m), 3.57-3.68 (5H, m ), 4.16-4.31 (2H, m), 5.11 (1H, t), 6.987.19 (1H, m), 7.83 (1H, dd), 8.16 (1H, td) , 8.30 (1H, dd), 8.50 (1H, s), 8.60 (1H, s), 8.77 (1H, s). Mass spectrum: m/z (ES+)[M+H]+ = 379.2. Intermediate A2: 8-Bromo-3-methyl-1-(oxan-4-yl)imidazo[5,4-c]quinoline - 2-one

[00402] A solution of sodium hydroxide (10.34 g, 258.48 mmol) in water (900 mL) was added to a stirred mixture of 8-bromo-1-(oxan-4-yl)-3H-imidazo [4,5-c]quinolin-2-one (60.0 g, 172.32 mmol), iodomethane (48.9 g, 344.63 mmol) and tetrabutylammonium bromide (5.55 g, 17.23 mmol ) in DCM (1500 mL) at room temperature under airflow. The resulting mixture was stirred for 16 hours, then the DCM was removed under reduced pressure. The precipitate was collected by filtration, washed with water (200 mL) and dried under vacuum to provide the desired material (58.0 g, 93%) as a brown solid, which was used without further purification. NMR spectrum: 1H NMR (400 MHz, CDCl3) δ 1.81-1.98 (2H, m), 2.82-3.00 (2H, m), 3.60 (3H, s), 3, 63 (2H, td), 4.05-4.35 (2H, m), 4.93 (1H, t), 7.69 (1H, dd), 8.03 (1H, d), 8.36 (1H, s), 8.71 (1H, s). Mass spectrum: m/z (ES+)[M+H]+ = 364.

[00403] On a larger scale, 8-bromo-1-(oxan-4-yl)-3H-imidazo[4,5-c]quinolin-2-one (1300 g, 3.73 mol) was loaded into the vessel along with tetrabutylammonium bromide (130 g, 0.40 mol) and 2-MeTHF (20.8 L). A solution of NaOH (240 g, 6.00 mol) in water (20.8 L) was then added over 5 minutes with exotherm observed from 18-24 °C. The biphasic mixture was heated to 42-48 °C before adding methyl iodide (465 mL, 7.47 mol) as a solution in 2-MeTHF (930 mL). The reaction was stirred at 45°C for 17 hours, at which point HPLC analysis showed 2.9% starting material and 97.1% product. The reaction mixture was combined with that of the other batches obtained on a larger scale for concentration in vacuo. The resulting aqueous suspension was then returned to the vessel and slurried for 1 hour with the product material obtained from the development batches combined at this time. The product was then isolated by filtration, washing with water (2 x 12 L) before drying in a vacuum oven at 40°C. In total, 3479 g of 8-bromo-3-methyl-1-(oxan-4-yl)imidazo[5,4-c]quinolin-2-one were isolated. Analytical data were compatible with those obtained from previous batches.Intermediate A3: 8-Bromo-1-(oxan-4-yl)-3H-imidazo[4,5-c]quinolin-2-one

[00404] Triethylamine (143 mL, 1025.07 mmol) was added to 6-bromo-4-(oxan-4-ylamino)quinoline-3-carboxylic acid (120 g, 341.69 mmol) in DMF (600 mL) at room temperature under airflow. The resulting mixture was stirred for 30 minutes, then diphenyl phosphorazidate (113 g, 410.03 mmol) was added. The resulting mixture was stirred for 30 minutes at room temperature, then at 60 °C for 2 hours. The solvent was removed under reduced pressure and the reaction mixture diluted with water. The precipitate was collected by filtration, washed with water (250 mL) and dried under vacuum to provide the desired material (120 g, 101%) as a brown solid, which was used without further purification. NMR spectrum: 1H NMR (400 MHz, DMSO-d6) δ 1.72-1.95 (2H, m), 2.59-2.80 (2H, m), 3.58 (2H, td), 3.98-4.11 (2H, m), 4.75-5.04 (1H, m), 7.75 (1H, dd), 7.97 (1H, d), 8.43 (1H, s), 8.71 (1H, s), 11.71 (1H, s). Mass spectrum: m/z (ES+)[M+H]+ = 348.

[00405] On a larger scale, 6-bromo-4-(oxan-4-ylamino)quinoline-3-carboxylic acid (2011 g, (2005 g of active), 5.71 mol) was added to the vessel with DMF ( 18.2 L). Triethylamine (4.7 L, 33.72 mol) was added with an endotherm observed from 21-18 °C. Diphenyl phosphorazidate (1600 mL, 7.42 mol) was added over 10 minutes with exotherm observed from 21°C to 23°C throughout the addition. The exotherm continued with the batch reaching 55°C after 1 hour (jacket held at 30°C) with gas evolution. The reaction initially proceeded in solution with a precipitate then forming after ~30 minutes. Once the temperature was established, the batch was analyzed by HPLC showing consumption of starting material and 99% product. The batch was heated to 60 °C for h, again HPLC indicating consumption of starting material and 98% product. The batch was concentrated in vacuo to minimal volume (~3 volumes), the residue being added to water (17 L) and rinsed with an additional portion of water (10 L). The mixture was slurried for 1 hour, filtered and washed with water (2x 17 L). The solid was then returned to the vessel and slurried in saturated NaHCO 3 solution (10 L) and MeOH (495 mL) for 1 hour. The solid was collected by filtration, washed with water (2x 3.5 L) and then dried in a vacuum oven at 40 °C for 116 hours to obtain 2023 g of the desired material. Analytical data were consistent with those obtained from previous batches.Intermediate A4: 6-Bromo-4-(oxan-4-ylamino)quinoline-3-carboxylic acid

[00406] A solution of sodium hydroxide (79 g, 1977.60 mmol) in water (1500 mL) was added to a stirred mixture of sodium 6-bromo-4-(oxan-4-ylamino)quinoline-3-carboxylate ethyl acetate (150 g, 395.52 mmol) in MeOH (1500 mL) at room temperature under air flow. The resulting mixture was stirred at 70°C for 2 hours, then the solvent was removed under reduced pressure. The reaction mixture was adjusted to pH=3 with 2M hydrochloric acid. The precipitate was collected by filtration, washed with water (500 mL) and dried under vacuum to provide the desired material (120 g, 86%) as a white solid, which was used without further purification. NMR spectrum: 1H NMR (400 MHz, DMSO-d6) δ 1.75-1.82 (2H, m), 2.05-2.09 (2H, m), 3.85-3.94 (5H , m), 7.95 (1H, d), 8.18 (1H, d), 8.65 (1H, s), 9.01 (1H, s). Mass spectrum: m/z (ES+)[M+H]+ = 351.1.

[00407] On a larger scale, ethyl 6-bromo-4-(oxan-4-ylamino)quinoline-3-carboxylate (1925 g, 5.08 mol) was charged into the vessel with EtOH (12.5 L). 2M NaOH (12.5 L, 25.03 mol) was then added with an exotherm from 22-35 °C during the addition for 20 minutes. The batch was heated to 70-80 °C for 17 hours, at which point HPLC indicated 98.3% product and <1% starting material. The batch was concentrated in vacuo to remove EtOH and returned to the vessel. A 2M HCl solution (13 L) was then added until pH 5-6 was achieved while maintaining the batch temperature below 50 °C. An exotherm was observed from 20-32°C over the 40 minute addition period. A precipitate formed and was slurried at 20-25 °C for 1.5 h before filtering, washing with water until the pH was neutral (3x 7 L). The collected solid was dried under vacuum at 70 °C to provide 1794 g of the desired material. Analytical data were compatible with those obtained from previous batches.Intermediate A5: Ethyl 6-bromo-4-(oxan-4-ylamino)quinoline-3-carboxylate

[00408] DIPEA (139 mL, 794.75 mmol) was added to ethyl 6-bromo-4-chloroquinoline-3-carboxylate (100 g, 317.90 mmol) and tetrahydro-2H-pyran-4-amine (35.4 g, 349.69 mmol) in DMA (1000 mL) at room temperature under air flow. The resulting mixture was stirred at 60°C for 16 hours, then the solvent was removed under reduced pressure. The mixture was azeotroped twice with toluene to provide the desired material (150 g, 124%) as a brown solid, which was used without further purification. NMR spectrum: 1H NMR (400 MHz, DMSO-d6) δ 1.36 (3H, t), 1.58-1.75 (2H, m), 1.902.02 (2H, m), 3.40 ( 2H, t), 3.81-3.98 (2H, m), 3.98-4.19 (1H, m), 4.37 (2H, q), 7.82 (1H, d), 7 .92 (1H, dd), 8.56 (1H, s), 8.86 (1H, s). Mass spectrum: m/z (ES-)[M-H]- = 378, 380.

[00409] On a larger scale, ethyl 6-bromo-4-chloroquinoline-3-carboxylate (2196 g, (1976 g active), 6.28 mol) was charged into the vessel with DMA (16 L). Tetrahydro-2H-pyran-4-amine (1224 g, 12.10 mol) was added over 10 minutes with an observed exotherm of 21-27 °C. DIPEA (3.5 L, 20.09 mol) was added with no exotherm observed. The mixture was heated to 75-85°C and the resulting solution stirred for 18.5 hours at 80°C. HPLC analysis indicated consumption of starting material and 99.2% product. The reaction was cooled to 50 °C and then poured into water (50 L). The resulting suspension was stirred for 2 hours at room temperature and the solids isolated by filtration and washing with water (8 L, then 2 x 4L). The solid was dried under vacuum at 40 °C for 55 hours to provide 2307 g of the desired material. Analytical data were consistent with those obtained from previous batches.Intermediate A6: Ethyl 6-bromo-4-chloroquinoline-3-carboxylate

[00410] DMF (0.119 mL, 1.54 mmol) was added to ethyl 6-bromo-1-[(4-methoxyphenyl)methyl]-4-oxoquinoline-3-carboxylate (160 g, 384.37 mmol) in thionyl chloride (800 mL) at room temperature under air flow. The resulting mixture was stirred at 75°C for 16 hours, then the solvent was removed under reduced pressure. The resulting mixture was azeotroped twice with toluene, then n-hexane (500 ml) added. The precipitate was collected by filtration, washed with n-hexane (200 mL) and dried under vacuum to provide the desired material (100 g, 83%) as a brown solid. NMR spectrum: 1H NMR (400 MHz, CDCl3) δ 1.47 (3H, t), 4.51 (2H, q), 7.95 (1H, dd), 8.11 (1H, d), 8 .60 (1H, d), 9.24 (1H, s). Mass spectrum: m/z (ES+)[M+H]+ = 314, 316.

[00411] On a larger scale, ethyl 6-bromo-1-[(4-methoxyphenyl)methyl]-4-oxoquinoline-3-carboxylate (5765 g, 13.85 mol) was charged into the vessel with thionyl chloride ( 28.8L). An exotherm was observed from 20-26 °C. DMF (4.4 mL) was added with no exotherm observed, and the batch heated to 75°C and stirred for 17 hours. HPLC analysis showed that 1.3% of the starting material remained with 98.0% product. The reaction was concentrated in vacuo and the residue azeotroped with toluene (25 L). The resulting solid was then slurried with heptane (18.5 L) for 2.5 hours, filtered and washed with heptane (3 x 4 L). The solid was dried under vacuum at 35 °C to provide 4077 g of the desired material (93% crude yield) which contained ~5% 6-bromo-1-[(4-methoxyphenyl)methyl]-4-oxoquinoline-3 ethyl -carboxylate plus ~4% hydrolysis product by HPLC (90% pure). The crude material (4077 g) was returned to the vessel and reprocessed with thionyl chloride (14.5 L) and DMF (2.2 mL). The mixture was heated to 75°C for 40 hours. The thionyl chloride was removed in vacuo and the residue azeotroped with toluene (10 L). The residue was slurried with heptane (18 L) for ~16 hours at 20 °C. The solid was collected by filtration, a portion being filtered under nitrogen and washed with heptane (3 L) to yield 2196 g of the desired material (90% by NMR assay, 99% by HPLC). The remainder of the batch was filtered under flowing air and washed with heptane (3 L) yielding 1905 g of the desired material (88% by NMR assay, 99% by HPLC). The yellow solids were combined for further work-up (4101 g, 3653 g active, 83% yield, 99% by HPLC). Intermediate A7: 6-Bromo-1-[(4-methoxyphenyl)methyl]-4-oxoquinoline- ethyl 3-carboxylate

[00412] DBU (102 mL, 679.62 mmol) was added dropwise to ethyl 2-(5-bromo-2-fluorobenzoyl)-3-[(4-methoxyphenyl)methylamino]prop-2-enoate (296 .5 g, 679.62 mmol), in acetone (1.2 L) at room temperature over a period of 2 minutes. The resulting solution was stirred for 16 hours, then the solid was filtered off and washed with MTBE to provide the desired material (180 g, 64%) as a pale yellow solid. NMR spectrum: 1H NMR (400 MHz, DMSO-d6) δ 1.30 (3H,t), 3.71 (3H,s), 4.25 (2H,q), 5.60 (2H,s) , 6.90-6.95 (2H, m), 7.12-7.25 (2H, m), 7.67 (1H, d), 7.80-7.90 (1H, m), 8 .30 (1H, d), 8.92 (1H, s). Mass spectrum: m/z (ES+)[M+H]+ = 418.

[00413] On a larger scale, ethyl 2-(5-bromo-2-fluorobenzoyl)-3-[(4-methoxyphenyl)methylamino]prop-2-enoate (8434 g, (7730 g of assumed active), 17 .71 mol) was charged into the vessel with acetone (23.2 L) at 15 °C. DBU (2.8 L, 18.72 mol) was added over 25 minutes with exotherm observed from 18-23 °C during addition. A precipitate formed after ~25 minutes and the batch continued to exotherm peaking at 37°C after 1 hour. The reaction was stirred at 20°C for 16.5 hours, at which point HPLC analysis indicated consumption of starting material and 96.5% product. The resulting precipitate was collected by filtration and washing with TBME (4x 3.4 L). The solid was then dried under vacuum at 40 °C to provide 6033 g of the desired material as a white solid (81.6% yield over 3 steps, 99.8% purity by HPLC). The analytical data were compatible with those obtained in previous batches. Intermediate A8: Ethyl 2-(5-bromo-2-fluorobenzoyl)-3-[(4-methoxyphenyl)methylamino]prop-2-enoate

[00414] (E)-ethyl 3-(dimethylamino)acrylate (98 g, 685.00 mmol) was added portionwise to 5-bromo-2-fluorobenzoyl chloride (163 g, 685 mmol) and DIPEA (120 mL , 685.00 mmol) in toluene (800 mL) at 10 °C over a period of 10 minutes. The resulting solution was stirred at 70 °C for 16 hours, then allowed to cool. (4-Methoxyphenyl)methanamine (94 g, 685 mmol) was added to the mixture over a period of 20 minutes at room temperature. The resulting solution was stirred for 3 h, then the reaction mixture was diluted with DCM (4 L) and washed with water (3 x 1 L). The organic phase was dried with Na2SO4, filtered and evaporated to give the desired material (300 g, 100%) as a brown oil, which was used immediately in the subsequent reaction without further purification. Mass spectrum: m/z (ES+)[M+H]+ = 436.

[00415] On a larger scale, 5-bromo-2-fluorobenzoyl chloride (4318 g, 4205 g of active, 17.71 mol) was charged into the vessel as a solution in toluene (7.5 L). DIPEA (3150 mL, 18.08 mol) was added with no observed exotherm. Ethyl-3-(dimethylamino)acrylate (2532 g, 17.71 mol) was added portionwise over 30 minutes maintaining the batch temperature <40°C. An exotherm from 21-24°C was observed over the 30 minute addition with a slow rise to 38°C over 1 hour. The reaction was stirred at 20-30°C for 16.5 hours. 4-Methoxybenzylamine (2439 g, 17.78 mol) was added portionwise over 30 minutes maintaining the batch temperature <40°C. An exotherm of 25-30 °C was observed during the addition with cooling provided by a reduced jacket temperature of 15 °C. The reaction was stirred for 4 hours at 20-30 °C, after which time HPLC analysis indicated 93.2% of the desired material. The batch was split for routine laboratory work with each half of the mixture diluted with DCM (28.6 L) and washed with water (3 x 7.8 L). The organic phases were dried with MgSO4 (~550 g), filtered and washed with DCM (4 L). The combined organic phases were then concentrated to provide 8444 g of the desired material as an oil (8434 g, 106% yield, 94.7% HPLC purity). Analytical data were consistent with those obtained from previous batches.Intermediate A9: 5-Bromo-2-fluorobenzoyl chloride

[00416] Thionyl chloride (75.0 mL, 1027.36 mmol) was added dropwise to 5-bromo-2-fluorobenzoic acid (150 g, 684.91 mmol) in toluene (1.2 L) and DMF (12 mL) at room temperature over a period of 1 hour. The resulting mixture was stirred at 70 °C for 16 hours, then the mixture was allowed to cool and concentrated in vacuo to provide the desired material (160 g, 98%) as pale yellow, which was used without further purification. NMR spectrum: 1H NMR (400 MHz, DMSO-d6) δ 7.26 - 7.31 (1H, m), 7.83 (1H, dd), 8.02 (1H, d).

[00417] On a larger scale, 3-bromo-6-fluorobenzoic acid (3888 g, 17.75 mol) was charged into the vessel at 20 °C followed by toluene (29.2 L). Thionyl chloride (1950 mL, 26.88 mol) was added, followed by DMF (310 mL) with no exotherm observed. The mixture was heated to 65-75°C (solution obtained above ~45°C) with no observed exotherm and slight gas evolution. The reaction was stirred for 40 hours at this temperature, at which point HPLC analysis showed 87.6% product, 3.4% starting material. The reaction was concentrated in vacuo and azeotroped with toluene (18 L) to provide 4328 g of the desired material (103% yield, 87.3% by HPLC).

[00418] 8-[6-(3-dimethylaminopropoxy)pyridin-3-yl]-3-methyl-1-(oxan-4-yl)imidazo[5,4-c]quinolin-2-one can also be prepared directly from 8-bromo-3-methyl-1-(oxan-4-yl)imidazo[5,4-c]quinolin-2-one as follows: 8-[6-(3-dimethylaminopropoxy)pyridin- 3-yl]-3-methyl-1-(oxan-4-yl)imidazo[5,4-c]quinolin-2-one

[00419] Chloro(2-dicyclohexylphosphine-2',4',6'-triisopropyl-1,1-biphenyl)[2-(2-amino-1,1-biphenyl)]palladium (II) (0.070 g , 0.09 mmol) was added to 8-bromo-3-methyl-1-(oxan-4-yl)imidazo[5,4-c]quinolin-2-one (3.2 g, 8.83 mmol) , K2CO3 (3.66 g, 26.50 mmol) and N,N-dimethyl-3-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin- 2-yl]oxypropan-1-amine (3.25 g, 10.60 mmol) in 1,4-dioxane (80 mL) and water (15 mL) under nitrogen. The resulting mixture was stirred at 90°C for 2 hours. The reaction mixture was concentrated, diluted with EtOAc (500 mL) and washed sequentially with water (2 x 100 mL) and saturated brine (100 mL). The organic layer was dried with Na2SO4 and filtered, the volume being reduced to approximately 80 mL under vacuum. The precipitate was collected by filtration, washed with Et2O (10 mL) and dried under vacuum to provide the desired material (2.80 g, 68.7%) as a white solid. Analytical data compatible with the material synthesized by alternative route.

[00420] On a larger scale, 8-bromo-3-methyl-1-(oxan-4-yl)imidazo[5,4-c]quinolin-2-one (1700.1 g) was suspended in EtOH (20 .4 L) in a 50 L vessel, then K2CO3 (1948.7 g) and N,N-dimethyl-3-[5-(4,4,5,5-tetramethyl-1,3 ,2-dioxaborolan-2-yl)pyridin-2-yl]oxypropan-1-amine (1731.4 g). EtOH (6.8 L) and purified water (5.1 L) were added to the mixture followed by the addition of chloro(2-dicyclohexylphosphine-2',4',6'-triisopropyl-1,1'-biphenyl) [2-(2'-amino-1,1'-biphenyl)] palladium(II) (37.3 g). The mixture was heated to reflux (77-80 °C) and stirred for 30 minutes at reflux, then cooled to 20 °C before being distilled under reduced pressure to a volume of 12.6 L. The batch was then cooled to 15 -25 °C and purified water (19.9 L) was added. The batch was stirred for 1 hour 5 minutes, filtered and the filter cake washed with purified water (3 x 3.7L) then dried under vacuum at 40°C to provide the desired crude material (1978 g, 91 .3%). The reaction was repeated on a similar scale to provide an additional 2084 g of crude material. Purification of crude 8-[6-(3-dimethylaminopropoxy)pyridin-3-yl]-3-methyl-1-(oxan-4-yl)imidazo[5,4-c]quinolin-2-one (2066, 9 g) was performed and 6 servings of 350 g or less. Crude 8-[6-(3-dimethylaminopropoxy)pyridin-3-yl]-3-methyl-1-(oxan-4-yl)imidazo[5,4-c]quinolin-2-one (350.1 g) was charged into a 10 L flask with EtOH (7.7 L) and heated until a solution was formed (6873 °C). Activated charcoal (35 g) was added and the solution stirred at 7075°C for 1 hour. The hot solution was filtered using a 3 porosity sinter funnel through a pad of celite (~40 g) in small portions to ensure that the product remained in solution. The celite pad was washed with hot EtOH (2 L) to remove any residual product on the celite, and the initial filtrate was charged to the vessel and the washed filtrate was stored in a carboy. This process was repeated with the other portions of the raw material. After the 6 hot filtrations over two days were completed, the filtrate in the vessel was distilled under reduced pressure until the remaining filtrate (held in a carboy) could be added. The batch was then heated until a solution formed (69 °C), and the distillation then continued until the volume in the vessel was equal to 5 volumes of the inserted material (maximum temperature of the batch at distillation = 55 °C). Distillation was stopped and the batch cooled to 5-15 °C, filtered, washed with EtOH (2.3 L) and dried to provide pure desired product (1926 g, 93.2% yield).

[00421] Analytical data compatible with the material synthesized via alternatives / different scales.

[00422] Intermediate A3, 8-Bromo-1-(oxan-4-yl)-3H-imidazo[4,5-c]quinolin-2-one, can also be prepared as follows: Intermediate A3: 8- Bromo-1-(oxan-4-yl)-3H-imidazo[4,5-c]quinolin-2-one

[00423] 1,3,5-Trichloro-1,3,5-triazinane-2,4,6-trione (18.9 g, 81.9 mmol) was added portionwise to a mixture of 6-bromo-4 -(oxan-4-ylamino)quinoline-3-carboxamide (57.3 g, 163.7 mmol) and DBU (54.7 g, 360.1 mmol) in MeOH (500 mL) at 0 °C. The resulting mixture was allowed to warm up and stirred at room temperature for 30 minutes. The resulting mixture was evaporated to dryness and the residue triturated with a petroleum ether/EtOAc mixture (5:1, 1000 mL) to afford the desired material (46.0 g, 81%) as a yellow solid. NMR spectrum: 1H NMR (400 MHz, DMSO-d6) δ 1.55-1.64 (2H, m), 1.87-1.98 (2H, m), 3.28-3.42 (2H , m), 3.79-3.89 (2H, m), 3.95-3.98 (1H, m), 7.62 (1H, bs), 7.70-7.85 (2H, m ), 7.89 (1H, d), 8.12 (1H, bs), 8.60 (1H, s), 8.71 (1H, s). Intermediate A10: 6-bromo-4-(oxan-4-ylamino)quinoline-3-carboxamide

[00424] A mixture with 6-bromo-4-chloroquinoline-3-carboxamide (50 g, 175.4 mmol), tetrahydro-2H-pyran-4-amine (26.2 g, 193 mmol) and DIPEA ( 56.13 mL, 438.5 mmol) in DMA (500 mL) was stirred at 90 °C overnight. The mixture was allowed to cool and poured into water (1500 ml). The precipitate was filtered, washed with water (2 x 200 mL) and dried under reduced pressure to provide the desired material (57.3 g, 93%) as a white solid. NMR spectrum: 1H NMR (400 MHz, DMSO-d6) δ 2.88 - 1.92 (2H, m), 2.59 - 2.78 (2H, m), 3.50 - 3.62 (3H , m), 3.96-4.08 (2H, m), 4.92-4.98 (1H, m), 7.80 (1H, m), 7.99 (1H, dd), 8, 46 (1H, d), 8.74 (1H, s). Intermediate A11: 6-Bromo-4-chloroquinoline-3-carboxamide

[00425] DMF (1.506 mL, 19.37 mmol) was added to 6-bromo-4-oxo-1H-quinoline-3-carboxylic acid (51.93 g, 193.72 mmol) and thionyl chloride (353 mL , 4843.07 mmol) at room temperature and the resulting solution stirred at 70°C for 2 hours under an inert atmosphere. The resulting solution was evaporated to dryness and the residue azeotroped with toluene to give 6-bromo-4-chloroquinoline-3-carbonyl chloride (62.13g). 6-Bromo-4-chloroquinoline-3-carbonyl chloride was dissolved in DCM (420 mL) and added portionwise to ammonium hydroxide (251 mL, 1937.23 mmol) at 0 °C over 15 minutes. The organic solvent was removed under reduced pressure and the solid collected by filtration, washed with water, Et2O and then dried to give the desired material (52.8 g, 95%) as a white solid. NMR spectrum: 1H NMR (500 MHz, DMSO-d6) δ 8.00 - 8.11 (3H, m), 8.24 (1H, s), 8.45 (1H, s), 8.92 ( 1H, s). Mass spectrum: m/z (ES+)[M+H]+ = 287. Intermediate A12: 6-Bromo-4-oxo-1H-quinoline-3-carboxylic acid

[00426] 2N Sodium hydroxide (506 mL, 1011.43 mmol) was added to a stirred suspension of ethyl 6-bromo-4-oxo-1H-quinoline-3-carboxylate (59.9 g, 202.29 mmol ) in EtOH (590 mL) and the resulting solution stirred at 75 °C for 1.5 h. Water was added and the mixture was cooled to 0 °C. The pH of the solution was adjusted to 3 using hydrochloric acid and the precipitate collected by filtration. The solid was washed with water, EtOH/water (1:1) then Et2O before being dried to give the desired material (51.9g, 96%) as a beige solid. NMR spectrum: 1H NMR (500 MHz, DMSO-d6) δ 7.80 (1H, d), 8.05 (1H, d), 8.37 (1H, s), 8.93 (1H, s) . Mass spectrum: m/z (ES+)[M+H]+ = 270. Intermediate A13: Ethyl 6-bromo-4-oxo-1H-quinoline-3-carboxylate

[00427] Diphenyl ether (870 mL) was heated to 240 °C, then diethyl 2-[[(4-bromophenyl)amino]methylidene]propanedioate (75 g, 219.18 mmol) was added in portions. The mixture was stirred at 240°C for 60 minutes in a flask equipped with a Dean-Stark apparatus. After cooling (25 °C), a crystallized solid formed. The mixture was diluted with Et2O and the solid was collected by filtration, washed with Et2O and dried to afford the desired material (59.9 g) as a beige crystallized solid, which was used without purification or characterization. Intermediate A14: 2 Diethyl -[[(4-bromophenyl)amino]methylidene]propanedioate

[00428] Diethyl 2-(ethoxymethylene)malonate (71.5 mL, 354.02 mmol) was added to 4-bromoaniline (42 g, 244.15 mmol) in EtOH (420 mL) and the resulting mixture stirred at 78 °C °C overnight. After cooling to 10 °C, the white solid was collected by filtration, washed with heptane and dried to provide the desired material (75 g, 90%) as a white crystallized solid. NMR spectrum: 1H NMR (500 MHz, DMSO-d6) δ 1.25 (6H, s), 4.10 - 4.27 (4H, m), 7.38 (2H, d), 7.57 ( 2H, d), 8.37 (1H, bs). Mass spectrum: m/z (ES+)[M+H]+ = 344.

[00429] The preparation of N,N-dimethyl-3-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl]oxypropan-1- amine is described below. N,N-Dimethyl-3-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl]oxypropan-1-amine

[00430] Butyllithium (2.5 N, 4.8 mL, 50.96 mmol) was added to a solution of 3-(5-bromopyridin-2-yl)oxy-N,N-dimethylpropan-1-amine (2.07 g, 7.99 mmol) and 4,4,5,5-tetramethyl-2-(propan-2-yloxy)-1,3,2-dioxaborolane (2.79 g, 15.00 mmol) in THF (20 mL) at -78 °C over 10 minutes under an inert atmosphere. The resulting solution was stirred for 4 hours at 18 °C. The reaction was then stopped by the addition of a saturated aqueous ammonium chloride solution, then partitioned between EtOAc (100 mL) and water (100 mL). The organic layer was concentrated in vacuo and the residue purified by FCC, eluting with EtOAc/petroleum ether (1:3) to provide the desired material (270 mg, 11%) as a yellow solid. Mass spectrum: m/z (ES+)[M+H]+ = 225.3-(5-Bromopyridin-2-yl)oxy-N,N-dimethylpropan-1-amine

[00431] 3-(Dimethylamino)propan-1-ol (3.09 g, 29.95 mmol) was added to a mixture of sodium hydride (2.4 g, 60.00 mmol) in DMF (50 mL) over a period of 20 minutes at room temperature. 5-Bromo-2-fluoropyridine (5.81 g, 33.01 mmol) was added and the resulting solution stirred for 4 hours at 30 °C. The reaction was then stopped by the addition of a saturated aqueous ammonium chloride solution and the resulting mixture concentrated under vacuum. The residue was purified by FCC, eluting with DCM/MeOH in Et2O (10:1) to provide the desired material (5.2 g, 67%) as a yellow oil. Mass spectrum: m/z (ES+)[M+H]+ = 259. Example 2 8-[6-(3-dimethylaminopropoxy)pyridin-3-yl]-1-( cis -3-methoxycyclobutyl)-3- methylimidazo[4,5-c]quinolin-2-one

[00432] Pd(Ph3P)4 (2.074 g, 1.79 mmol) was added to a mixture of 8-bromo-1-(cis-3-methoxycyclobutyl)-3-methylimidazo[4,5-c]quinoline-2 -one (13 g, 35.89 mmol), N,N-dimethyl-3-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2- yl]oxypropan-1-amine (13.15 g, 43.07 mmol) and cesium carbonate (23.39 g, 71.78 mmol) in 1,4-dioxane (200 mL) and water (40 mL) under nitrogen. The resulting mixture was stirred at 90°C for 3 hours before being allowed to cool. The reaction mixture was concentrated, diluted with EtOAc (750 mL) and washed sequentially with water (2 x 150 mL) and saturated brine (150 mL). The organic layer was dried with Na2SO4, filtered and evaporated to give the crude product. The crude product was purified by FCC, gradient elution from 0 to 10% MeOH in DCM, providing the desired material (12.50 g, 75%) as a white solid. NMR spectrum: 1H NMR (400 MHz, DMSO-d6) δ 1.90 (2H, q), 2.16 (6H, s), 2.37 (2H, t), 2.72 - 2.92 ( 2H, m), 3.01 (2H, d), 3.21 (3H, s), 3.50 (3H, s), 3.79 - 3.95 (1H, m), 4.37 (2H , t), 5.12 (1H, t), 6.97 (1H, d), 7.82 - 7.98 (1H, m), 8.11 (1H, d), 8.19 (2H, dd), 8.42 (1H, s), 8.67 (1H, d), 8.87 (1H, s). Mass spectrum: m/z (ES+)[M+H]+ = 462.Intermediate B1:8-Bromo-1-( cis -3-methoxycyclobutyl)-3-methylimidazo[4,5-c]quinolin-2- ona

[00433] Methyl iodide (11.49 mL, 183.81 mmol) was added to a mixture of 8-bromo-1-(cis-3-methoxycyclobutyl)-3H-imidazo[4,5-c]quinolin-2 -one (32 g, 91.90 mmol), sodium hydroxide (5.51 g, 137.85 mmol) and tetrabutylammonium bromide (2.94 g, 9.19 mmol) in DCM (400 mL) and water ( 300 mL) and the resulting mixture stirred at room temperature for 12 hours. The DCM was removed in vacuo and the precipitate collected by filtration, washed with water (200 mL) and dried under vacuum to provide the desired material (25.00 g, 75%) as a pale yellow solid. NMR spectrum: 1H NMR (400 MHz, DMSO-d6) δ 2.72 - 2.86 (2H, m), 2.9 - 3.08 (2H, m), 3.22 (3H, s), 3.49 (3H, s), 3.85 - 3.89 (1H, m), 4.88 - 5.06 (1H, m), 7.74 (1H, dd), 7.98 (1H, dd). d), 8.50 (1H, d), 8.92 (1H, s). Mass spectrum: m/z (ES+)[M+H]+ = 362, 364. Intermediate B2: 8-Bromo-1-(cis -3-methoxycyclobutyl)-3H-imidazo[4,5-c]quinolin- 2-one

[00434] Triethylamine (39.3 mL, 281.89 mmol) was added to 6-bromo-4-[(cis-3-methoxycyclobutyl)amino]quinoline-3-carboxylic acid (33 g, 93.96 mmol) in DMF (200 mL) at room temperature. After stirring for 30 minutes, diphenyl phosphorazidate (28.4 g, 103.36 mmol) was added and the resulting mixture was stirred at 60 °C for 2 hours. The reaction mixture was poured into water (500 mL), the precipitate collected by filtration, washed with water (200 mL) and dried under vacuum to provide the desired material (32.0 g, 98%) as a yellow solid, which was used without further purification. NMR spectrum: 1H NMR (400 MHz, DMSO-d6) δ 2.75 - 2.82 (2H, m), 2.9 - 3.05 (2H, m), 3.22 (3H, s), 3.80 - 3.90 (1H, m), 4.85 - 4.99 (1H, m), 7.71 (1H, dd), 7.94 (1H, d), 8.48 (1H, d), 8.69 (1H, s), 10.42 (1H, s). Mass spectrum: m/z (ES+)[M+H]+ = 348, 350. Intermediate B3: 6-Bromo-4-[( cis -3-methoxycyclobutyl)amino]quinoline-3-carboxylic acid

[00435] Sodium hydroxide (190 mL, 379.70 mmol) was added to ethyl 6-bromo-4-[(cis-3-methoxycyclobutyl)amino]quinoline-3-carboxylate (36 g, 94.92 mmol) in a mixture of MeOH (120 mL) and THF (120 mL) and the resulting mixture stirred at 60°C for 3 hours. The solvent was removed under reduced pressure, the pH of the mixture being adjusted to 3 with 2M hydrochloric acid. The precipitate was collected by filtration, washed with water (300 mL) and dried under vacuum to provide the desired material (33.0 g, 99%) as a light yellow solid, which was used without further purification. Mass spectrum: m/z (ES+)[M+H]+ = 351. Intermediate B4: Ethyl 6-bromo-4-[( cis -3-methoxycyclobutyl)amino]quinoline-3-carboxylate

[00436] DIPEA (41.6 mL, 238.43 mmol) was added to ethyl 6-bromo-4-chloroquinoline-3-carboxylate (30 g, 95.37 mmol) and 3-methoxycyclobutan-1-amine hydrochloride (15.75 g, 114.44 mmol) in DMA (100 mL) and the resulting mixture stirred at 75°C for 5 hours. The solvent was removed under reduced pressure to provide the desired material (36.0 g, 100%) as a yellow solid, which was used without further purification. NMR spectrum: 1H NMR (300 MHz, DMSO-d6) δ 1.38 (3H, t), 1.85-1.98(2H, m), 2.75-7.89 (2H, m), 3.17 (3H, s), 3.65-3.78 (1H, m), 3.98-4.05 (1H, m), 4.35 (2H, q), 7.60 (1H, d), 7.70 (1H, dd), 8.40 (1H, d), 8.84-8.85 (1H, m). Mass spectrum: m/z (ES+)[M+H]+ = 379.

[00437] Intermediate B2: 8-Bromo-1-(cis-3-methoxycyclobutyl)-3H-imidazo[4,5-c]quinolin-2-one can also be prepared as follows.

[00438] DBU (5.36 mL, 35.86 mmol) was added in one portion to a mixture of 6-bromo-4-[(cis-3-methoxycyclobutyl)amino]quinoline-3-carboxamide (6.28 g , 17.93 mmol) and 1,3,5-trichloro-1,3,5-triazinane-2,4,6-trione (1.667 g, 7.17 mmol) in MeOH (65 mL). The resulting mixture was stirred at room temperature for 18 hours. The resulting mixture was evaporated to dryness and the residue purified by FCC with gradient elution from 0 to 10% MeOH in DCM, providing the desired material (6.48g, 104%). Data compatible with material produced by the alternative synthesis described above. Intermediate B5: 6-Bromo-4-[( cis -3-methoxycyclobutyl)amino]quinoline-3-carboxamide

[00439] DIPEA (13.76 mL, 78.80 mmol) was added to a mixture of 6-bromo-4-chloroquinoline-3-carboxamide (7.5 g, 26.27 mmol) and 3-methoxycyclobutane hydrochloride 1-amine (3.98 g, 28.89 mmol) in DMA (35 mL) and the resulting mixture stirred at 100°C for 18 hours. The reaction mixture was diluted with water (250 mL) and the precipitate collected by filtration, washed with water (50 mL) and dried under vacuum to provide the desired material (6.28 g, 68.3%) as a tan solid , which was used without further purification. NMR spectrum: 1H NMR (400 MHz, DMSO-d6) δ 2.45 - 2.55 (2H, m), 2.76 - 2.88 (2H, m), 3.17 (3H, s), 3.66 (1H, q), 4 - 4.16 (1H, m), 7.67 (1H, s), 7.80 (1H, dd), 7.93 (1H, dd), 8.15 (1H, s), 8.59 (1H, s), 8.69 (1H, s), 9.34 (1H, s). Mass spectrum: m/z (ES+)[M+H]+ = 350, 352. Example 3 8-[6-(3-dimethylaminopropoxy)pyridin-3-yl]-7-fluoro-3-methyl-1- (4-methyloxan-4-yl)imidazo[5,4-c]quinolin-2-one

[00440] 8-Bromo-7-fluoro-3-methyl-1-(4-methyloxan-4-yl)imidazo[5,4-c]quinolin-2-one (0.13 g, 0.33 mmol) was added to N,N-dimethyl-3-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl]oxypropan-1-amine (0.121 g, 0.40 mmol), cesium carbonate (0.322 g, 0.99 mmol) and Pd(Ph3P)4 (0.038 g, 0.03 mmol) in 1,4-dioxane (5 mL) and water (1 mL ) under nitrogen. The resulting mixture was stirred at 80°C for 2 hours. The crude product was purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5 µm silica, 19 mm diameter, 100 mm length) using mixtures of decreasing polarity water (containing 0.1% NH3) and MeCN as eluents . Fractions containing the desired compound were evaporated to dryness to provide the desired material (0.050g, 30.8%) as a white solid. NMR spectrum: 1H NMR (400 MHz, DMSO-d6) δ 1.82-2.10 (7H, m), 2.18 (6H, s), 2.35-2.50 (2H, m), 3.0-3.1 (2H, m), 3.31-3.39 (2H, m), 3.35 (3H, s), 3.61-3.74 (2H, m), 4, 36 (2H, t), 6.99 (1H, d), 7.97 (1H, d), 8.01 (1H, dt), 8.39 (1H, d), 8.45 (1H, d ), 8.97 (1H, s). Mass spectrum: m/z (ES+)[M+H]+ = 494.

[00441] The following compounds were synthesized analogously, using the appropriate boronic ester and the appropriate bromide: 1 Reaction stirred for 18 hours at 80 °C. This compound can also be isolated as the methanesulfonic acid salt by dissolving the free base in DCM, treating with methanesulfonic acid (~1.1 eq), concentrating in vacuo, and triturating the residue with Et2O. 2 * Reaction stirred for 2 hours at 90 °C. 3 ** Reaction stirred for 75 minutes at 120 °C. 4 *** The reaction used tert-butyl 8-bromo-1-(oxan-4-yl)-2-oxoimidazo[5,4-c]quinoline-3-carboxylate as a starting material and was stirred at 90° C for 2 hours. The crude material was purified by preparative HPLC using mixtures of water of decreasing polarity (containing 0.3% formic acid) and MeCN as eluents. No additional deprotection step was necessary. 5 **** Reaction performed using chloro(2-dicyclohexylphosphine-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl) ]palladium(II) as the catalyst and stirred at 100°C for 3 hours. 6 ***** Reaction stirred for 1 hour at 100 °C.

[00442] Example 4: NMR spectrum (free base): 1H NMR (500 MHz, DMSO-d6) δ 1.90 (2H, p), 2.18 (6H, s), 2.35 - 2.43 (2H, m), 3.55 (3H, s), 4.37 (2H, t), 5.07 (2H, dd), 5.28 (2H, t), 6.13 - 6.24 ( 1H, m), 6.97 (1H, d), 7.98 (1H, dd), 8.15 (1H, d), 8.17 - 8.27 (1H, m), 8.50 (1H , d), 8.69 (1H, d), 8.94 (1H, s). NMR spectrum (methanesulfonic acid salt): 1H NMR (500 MHz, DMSO-d6) δ 2.06 (2H, dt), 2.31 (3H, s), 2.59 (6H, s), 2.79 - 3.05 (2H, m), 3.55 (3H, s), 4.40 (2H, t), 5.07 (2H, dd), 5.27 (2H, t), 6 .14 - 6.24 (1H, m), 6.99 (1H, dd), 7.99 (1H, dd), 8.15 (1H, d), 8.25 (1H, dd), 8, 53 (1H, d), 8.70 (1H, dd), 8.94 (1H, s), 9.35 (1H, s). Mass spectrum: m/z (ES+)[M+H]+ = 433.6.

[00443] Example 5: NMR spectrum: 1H NMR (400 MHz, DMSO-d6) δ 1.87-1.92 (2H, m), 2.15 (6H, s), 2.38 (2H, t ), 2.78-2.98 (4H, m), 3.50 (3H, s), 4.01-4.19 (1H, m), 4.40 (2H, t), 4.92 ( 1H, p), 5.26 (1H, d), 6.97 (1H, d), 7.92 (1H, dd), 8.11 (1H, d), 8.20 (1H, dd), 8.41 (1H, s), 8.67 (1H, d), 8.85 (1H, s). Mass spectrum: m/z (ES+)[M+H]+ = 462.3.

[00444] Example 6: NMR spectrum: 1H NMR (300 MHz, DMSO-d6) δ 1.93 (2H, t), 2.22 (6H, s), 2.48 (2H, t), 2, 77-2.79 (2H, m), 2.93 - 3.02 (2H, m), 3.10 (3H, s), 3.49 (3H, s), 3.69-3.9 ( 1H, m), 4.37 (2H, t), 5.06 (1H, p), 6.98 (1H, d), 7.90 (1H, d), 8.04 (1H, dd), 8.37 (1H, d), 8.50 (1H, d), 8.91 (1H, s). Mass spectrum: m/z (ES+)[M+H]+ = 480.

[00445] Example 7: NMR spectrum: 1H NMR (400 MHz, DMSO-d6) δ 1.92-1.98 (2H, m), 2.00 (3H, s), 2.01-2.07 (2H, m), 2.28 (6H, s), 2.50-2.54 (2H, m), 3.11 (2H, d), 3.36 (2H, t), 4.35- 4.38 (2H, m), 3.51 (3H, s), 4.36 (2H, t), 6.97 (1H, d), 7.90 (1H, dd), 8.11-8 .15 (2H, m), 8.47 (1H, s), 8.57 (1H, d), 8.95 (1H, s). Mass spectrum: m/z (ES+)[M+H]+ = 476.

[00446] Example 8: NMR spectrum: 1H NMR (400 MHz, DMSO-d6) δ 1.92-1.96 (4H, m), 2.23 (6H, s), 2.49-2.51 (2H, m), 2.62 - 2.75 (2H, m), 3.33 - 3.57 (5H, m), 4.05 (2H, dd), 4.37 (2H, t), 5.03-5.11 (1H, m), 6.98 (1H, d), 7.94 (1H, d), 8.08 (1H, dd), 8.34 (1H, d), 8 .54 (1H, s), 8.93 (1H, s). Mass spectrum: m/z (ES+)[M+H]+ = 480.

[00447] Example 9: NMR spectrum: 1H NMR (400 MHz, DMSO-d6) δ 1.85-1.91 (2H, m), 2.16 (6H, s), 2.37 (2H, t ), 3.53 (3H, s), 4.36 (2H, t), 5.01 (2H, t), 5.24 (2H, t), 6.13 (1H, p), 6.98 (1H, d), 7.93 (1H, d), 8.05 (1H, dd), 8.43 (1H, d), 8.50 (1H, s), 8.97 (1H, s) . Mass spectrum: m/z (ES+)[M+H]+ = 452.

[00448] Example 10: NMR spectrum: 1H NMR (500 MHz, DMSO-d6) δ 1.78 (2H, dd), 1.90 (2H, p), 2.17 (7H, s), 2, 38 (2H, t), 2.66 (1H, qd), 3.38 (1H, td), 3.49 (3H, s), 3.91 (1H, d), 4.12 (1H, dd ), 4.21 (1H, t), 4.38 (2H, t), 4.91 (1H, ddd), 7.01 (1H, d), 7.93 (1H, d), 8.06 (1H, dt), 8.26 (1H, d), 8.51 (1H, s), 8.92 (1H, s). Mass spectrum: m/z (ES+)[M+H]+ = 479.

[00449] Example 11: NMR spectrum: 1H NMR (500 MHz, DMSO-d6) δ 1.80 (2H, d), 1.90 (2H, p), 2.17 (7H, s), 2, 38 (2H, t), 2.61 - 2.73 (1H, m), 3.38 (1H, td), 3.50 (3H, s), 3.91 (1H, d), 4.12 (1H, dd), 4.21 (1H, t), 4.38 (2H, t), 4.86 - 4.98 (1H, m), 7.01 (1H, d), 7.94 ( 1H, d), 8.06 (1H, dt), 8.27 (1H, d), 8.52 (1H, s), 8.92 (1H, s). Mass spectrum: m/z (ES+)[M+H]+ = 479.

[00450] Example 12: NMR spectrum: 1H NMR (400 MHz, DMSO-d6) δ 1.89-1.91 (2H, m), 2.15 (6H, s), 2.35 (2H, t ), 2.78-2.83 (2H, m), 2.96-3.303 (2H, m), 3.19 (3H, s), 3.83 (1H, p), 4.36 (2H, t), 5.09 (1H, p), 6.97 (1H, d), 7.91 (1H, dd), 8.08 (1H, d), 8.20 (1H, dd), 8, 43 (1H, d), 8.65 (1H, d), 8.87 (1H, s), 11.54 (1H, bs). Mass spectrum: m/z (ES+)[M+H]+ = 448.

[00451] Example 13: NMR spectrum: 1H NMR (300 MHz, DMSO-d6) δ 1.85-1.92 (4H, m), 2.19 (6H, s), 2.40 (2H, t ), 2.69-2.75 (2H, m), 3.57 (2H, t), 4.04-4.09 (2H, m), 4.36 (2H, t), 5.08 ( 1H, p), 6.98 (1H, d), 7.94 (1H, dd), 8.10-8.21 (2H, m), 8.42 (1H, s), 8.65 (1H , s), 8.66 (1H, s), 11.57 (1H, s). Mass spectrum: m/z (ES+)[M+H]+ = 448.

[00452] Example 14: NMR spectrum: 1H NMR (300 MHz, DMSO-d6) δ 1.77-1.90(2H, m), 1.90-1.99 (2H, m), 2.47 -2.51 (2H, m), 2.722.91 (4H, m), 3.09 (4H, t), 3.50 (3H, s), 4.04-4.08 (1H, m), 4.33 (2H, t), 4.94 (1H, p), 5.24 (1H, d), 6.95 (1H, d), 7.92 (1H, dd), 8.11 (1H , d), 8.20 (1H, dd), 8.41 (1H, d), 8.66 (1H, d), 8.87 (1H, s). Mass spectrum: m/z (ES+)[M+H]+ = 460.

[00453] Example 15: NMR spectrum: 1H NMR (300 MHz, DMSO-d6) δ 1.67-1.70 (4H, m), 1.88-1.97 (2H, m), 2.44 -2.51 (4H, m), 2.542.56 (2H, m), 2.79-2.95 (4H, m), 3.49 (3H, s), 4.05-4.11 (1H , m), 4.37 (2H, t), 4.93 (1H, p), 5.24 (1H, d), 6.96 (1H, d), 7.92 (1H, dd), 8 .11(1H, d), 8.20 (1H, dd), 8.40 (1H, d), 8.66 (1H, d), 8.87(1H, s). Mass spectrum: m/z (ES+)[M+H]+ = 474.

[00454] Example 16: NMR spectrum: 1H NMR (300 MHz, DMSO-d6) δ 1.75 - 1.97 (4H, m), 2.10 - 2.22 (1H, d), 2.24 (6H, s), 2.42 - 2.55 (2H, m), 2.62 - 2.77 (1H, m), 3.34 - 3.45 (1H, m), 3.50 (3H, m) , s), 3.92 (1H, d), 4.10 - 4.26 (2H, m), 4.35 (2H, t), 4.89 - 5.02 (1H, m), 6, 98 (1H, d), 7.92 (1H, dd), 8.12 - 8.19 (2H, m), 8.33 (1H, s), 8.62 (1H, d), 8.89 (1H, s). Mass spectrum: m/z (ES+)[M+H]+ = 462.25.

[00455] Example 17: NMR spectrum: 1H NMR (300 MHz, DMSO-d6) δ 1.75 - 1.97 (4H, m), 2.10 - 2.28 (7H, m), 2.40 (2H, t), 2.62 - 2.77 (1H, m), 3.33 - 3.47 (1H, m), 3.50 (3H, s), 3.93 (1H, d), 4.10 - 4.26 (2H, m), 4.35 (2H, t), 4.91 - 5.05 (1H, m), 6.98 (1H, d), 7.95 (1H, dd), 8.12 - 8.19 (1H, m), 8.35 (1H, s), 8.62 (1H, d), 8.89 (1H, s). Mass spectrum: m/z (ES+)[M+H]+ = 462.25.

[00456] Example 18: NMR spectrum: 1H NMR (300 MHz, DMSO-d6) δ 1.85 - 2.00 (2H, m), 2.21 (6H, s), 2.46 (2H, t ), 2.74 - 2.87 (2H, m), 2.91 - 3.07 (2H, m), 3.18 (3H,s), 3.50(3H, s), 3.75 - 3.89(1H, m), 4.32 (2H, t), 4.91 - 5.08(1H, m), 6.94 (1H, d), 7.78 (1H, dd), 8 .10(1H, d), 8.16 - 8.27(1H, m), 8.45 (1H, s), 8.90 (1H, s); 19F NMR (300 MHz, DMSO-d6) δ 73.62, Mass spectrum: m/z (ES+)[M+H]+ = 480.

[00457] Example 19: NMR spectrum: 1H NMR (300 MHz, DMSO-d6) δ 1.88 - 2.00 (2H, m), 2.23 (6H, s), 2.41 - 2.50 (2H, m), 2.71 - 2.83 (2H, m), 2.89 - 3.03 (1H, m), 3.15 (3H, s), 3.49 (3H, s), 3.71 - 3.86 (1H, m), 4.33 (2H, t), 4.91 - 5.08 (1H, m), 6.97 (1H, d), 7.90 (1H, d), 8.12 (1H, dt), 8.43 (1H, dd), 8.92 (1H, s), 19F NMR (300 MHz, DMSO-d6) δ 71.56 ppm, 116.913 ppm. Mass spectrum: m/z (ES+)[M+H]+ = 498.

[00458] Example 20: NMR spectrum: 1H NMR (300 MHz, DMSO-d6) δ 1.79-1.90 (2H, m), 2.10-2.25 (3H, m), 2.60 -2.72 (1H, m), 2.73 (6H, s), 3.10-3.20 (2H, m), 3.30-3.47 (4H, m), 3.91 (1H , d), 4.10 (1H, d), 4.28 (1H, t), 4.39 (2H, t), 4.81-4.96 (1H, m), 6.99 (1H, t). d), 7.85 (1H,d), 8.14 (1H,d), 8.30 (1H, dd), 8.41 (1H, s), 8.91 (1H, s). Mass spectrum: m/z (ES+)[M+H]+ = 480.

[00459] Example 21: NMR spectrum: 1H NMR (300 MHz, MeOD) δ 1.94-204 (2H, m), 2.20-2.30 (2H, m), 2.82 (6H, s ), 2.82-3.00 (2H, m), 3.18-3.35 (2H, m), 3.62 (3H, s), 3.62-3.71 (2H, m), 4.20 (2H, dd), 4.50 (2H, t), 5.12-5.25 (1H, m), 6.95 (1H, d), 7.91 (1H, d), 8 .19 (2H, m), 8.64 (1H, d), 8.87 (1H, s). Mass spectrum: m/z (ES+)[M+H]+ = 480.

[00460] Example 22: NMR spectrum: 1H NMR (300 MHz, DMSO-d6) δ 1.75-1.99 (4H, m), 2.10-2.24 (7H, m), 2.35 -2.47 (2H, m), 2.552.69 (1H, m), 3.34-3.46 (1H, m), 3.92 (1H, d), 4.03 (1H, d), 4.24-4.97 (3H, m), 4.81-4.99 (1H, m), 6.97 (1H, d), 7.84 (1H, d), 8.13 (1H, d), 8.24 (1H, dd), 8.40 (1H, s), 8.90 (1H, s). Mass spectrum: m/z (ES+)[M+H]+ = 480.

[00461] Example 23: NMR spectrum: 1H NMR (400 MHz, DMSO-d6) δ 1.71 (4H, p), 1.78 (2H, d), 1.95 (2H, p), 2, 14 (1H, d), 2.53 - 2.74 (6H, m), 3.38 (2H, td), 3.49 (3H, s), 3.91 (1H, d), 4.12 (1H, dd), 4.21 (1H, t), 4.40 (2H, t), 4.91 (1H, t), 7.01 (1H, d), 7.94 (1H, d) , 8.06 (1H, dt), 8.26 (1H, d), 8.51 (1H, s), 8.92 (1H, s). Mass spectrum: m/z (ES+)[M+H]+ = 506.

[00462] Example 24: NMR spectrum: 1H NMR (400 MHz, DMSO-d6) δ 1.64 - 1.74 (4H, m), 1.78 (2H, d), 1.94 (2H, p ), 2.14 (1H, d), 2.46 (4H, d), 2.54 - 2.6 (1H, m), 2.61 - 2.73 (1H, m), 3.34 - 3.43 (2H, m), 3.49 (3H, s), 3.91 (1H, d), 4.07 - 4.17 (1H, m), 4.21 (1H, t), 4 .40 (2H, t), 4.84 - 4.98 (1H, m), 6.98 - 7.04 (1H, m), 7.93 (1H, d), 8.06 (1H, dt ), 8.26 (1H, d), 8.51 (1H, s), 8.92 (1H, s); Mass spectrum: m/z (ES+)[M+H]+ = 506.

[00463] The methods for preparing the bromine intermediates necessary for the synthesis of Examples 3 - 24 have already been described or were carried out as follows by methylation of the 3H-imidazo[4,5-c]quinolin-2 intermediates corresponding -one. Intermediate C1: 8-Bromo-7-fluoro-1-( cis -3-methoxycyclobutyl)-3-methylimidazo[4,5-c]quinolin-2-one

[00464] A solution of sodium hydroxide (4 g, 100 mmol) in water (240 mL) was added to a solution of 8-bromo-7-fluoro-1-(cis-3-methoxycyclobutyl)-3H-imidazo[ 4,5-c]quinolin-2-one (23 g, 62.81 mmol), methyl iodide (13.41 g, 94.48 mmol) and tetrabutylammonium bromide (2 g, 6.21 mmol) in DCM (400 mL) and the resulting solution stirred at room temperature overnight. The mixture was concentrated under vacuum and the solids collected by filtration. The crude product was recrystallized from DCM:EtOAc 1:2 and the solid dried in an oven under reduced pressure to provide the desired material (18 g, 75%) as an off-white solid. NMR spectrum: 1H NMR (300 MHz, DMSO-d6) δ 2.70-2.85(2H, m), 2.933.07(2H, m), 3.22(3H, s), 3.48( 3H, s), 3.73-4.00(1H, m), 4.86-5.15(1H, m), 7.75-8.07(1H, d), 8.52-8, 73(1H, d), 8.93(1H, s). Mass spectrum: m/z (ES+)[M+H]+ = 380.

[00465] The following intermediates were prepared analogously from the appropriate 3H-imidazo[4,5-c]quinolin-2-one intermediate: * The reaction had not proceeded to completion so more methyl iodide, sodium hydroxide and tetrabutylammonium bromide were added and the reaction was stirred for an additional 16 - 18 h. 2 * The reaction was stirred for 72 hours at room temperature.

[00466] Intermediate D1: NMR spectrum: 1H NMR (300 MHz, DMSO-d6) δ 1.82 - 1.88 (2H, m), 2.09 - 2.15 (1H, m), 2.55 -2.78 (1H, m), 3.30 - 3.47 (1H, m) 3.48 (3H, s), 3.92 (1H, d), 4.02 - 4.22 (2H, m), 4.68-4.88 (1H, m), 7.75 (1H, d), 7.99 (1H, d), 8.35 (1H, s), 8.92 (1H, s ). Mass spectrum: m/z (ES+)[M+H]+ = 362.2.

[00467] Intermediate E1: NMR spectrum: 1H NMR (300 MHz, DMSO-d6) δ 1.80-1.86 (2H, m), 2.07-2.12 (1H, m), 2.61 -2.75 (1H, m), 3.32-3.46 (1H, m), 3.47 (3H, s), 3.92-3.98 (1H, m), 4.01-4 .20 (2H,m), 4.72-4.83 (1H,m), 7.76 (1H,dd), 8.00 (1H,d), 8.34 (1H,d), 8, 92 (1H,s). Mass spectrum: m/z (ES+)[M+H]+ = 362, 364.

[00468] Intermediate F1: NMR spectrum: 1H NMR (400 MHz, DMSO-d6, 100°C) δ 1.88 (2H, d), 2.59 - 2.84 (2H, m), 3.50 (3H, s), 3.60 (2H, t), 4.06 (2H, d), 4.95 (1H, s), 7.90 (1H, d), 8.56 (1H, d) , 8.89 (1H, s). Mass spectrum: m/z (ES+)[M+H]+ = 381.96.

[00469] Intermediate G1: Mass spectrum: m/z (ES+)[M+H]+ = 352.

[00470] Intermediate H1: NMR spectrum: 1H NMR (400 MHz, DMSO-d6) δ 3.53 (3H, s), 5.01 (2H, dd), 5.22 (2H, t), 6 - 6.18 (1H, m), 7.77 (1H, dd), 8.00 (1H, d), 8.51 (1H, d), 8.97 (1H, s). Mass spectrum: m/z (ES+)[M+H]+ = 334, 336.

[00471] Intermediate H: NMR spectrum: 1H NMR (400 MHz, DMSO-d6, 100°C) δ 1.99 (3H, s), 2.00-2.04 (2H, m), 2.98 (1H, d), 3.13 - 3.16 (1H, m), 3.32 - 3.38 (2H, m), 3.53 (3H, s), 3.66 - 3.70 (2H, d) , m), 7.99 (1H, d), 8.63 (1H, d), 9.00 (1H, s) Mass spectrum: m/z (ES+)[M+H]+ = 394, 396 .

[00472] Intermediate J1: NMR spectrum: 1H NMR (400 MHz, DMSO-d6) δ 2.65-2.72 (2H, m), 2.85-2.93 (2H, m), 3.51 (3H, s), 4.024.09 (1H, m), 4.78 (1H, m), 5.26 (1H, d), 7.73 (1H, dd), 7.97 (1H, d) , 8.45 (1H, d), 8.92 (1H, s). Mass spectrum: m/z (ES+)[M+H]+ = 348.

[00473] Intermediate K1: NMR spectrum: 1H NMR (400 MHz, DMSO-d6) δ 1.88-190 (2H, m), 2.09 (1H, d), 2.70 (1H, ddd), 3.36 - 3.44 (1H, m), 3.47 (3H, s), 3.94 (1H, d), 4.07 (1H, dd), 4.15 (1H, t), 4 .79 (1H, ddd), 7.97 (1H, d), 8.48 (1H, d), 8.93 (1H, s). Mass spectrum: m/z (ES+)[M+H]+ = 380, 382.

[00474] Intermediate L1: NMR spectrum: 1H NMR (400 MHz, DMSO-d6) δ 1.86 (2H, dd), 2.11 (1H, d), 2.69 (1H, ddd), 3, 37 - 3.45 (1H, m), 3.48 (3H, s), 3.95 (1H, d), 4.08 (1H, dd), 4.18 (1H, t), 4.80 (1H, ddd), 7.98 (1H, d), 8.50 (1H, d), 8.94 (1H, s). Mass spectrum: m/z (ES+)[M+H]+ = 380, 382.

[00475] Intermediate M1, 8-bromo-3-methyl-1-(4-methyloxan-4-yl)imidazo[5,4-c]quinolin-2-one, was prepared as follows:

[00476] 1,1-Dimethoxy-N,N-dimethylmethanamine (1.663 mL, 12.42 mmol) was added to a stirred suspension of 8-bromo-1-(4-methyloxan-4-yl)-3H-imidazo[ 4,5-c]quinolin-2-one (0.9 g, 2.48 mmol) in DMF (8.28 mL) under an inert atmosphere and the reaction heated at 80 °C overnight. The reaction mixture was evaporated to dryness, the crude product being loaded dry onto silica and purified by FCC with gradient elution from MeOH 2 to 10% in DCM, providing the desired material (0.591 g, 63.2%) as a yellow solid. NMR spectrum: 1H NMR (400 MHz, DMSO-d6) δ 1.92 (3H, s), 2.02 (2H, ddd), 2.95 - 3.03 (2H, m), 3.36 ( 2H, td), 3.50 (3H, s), 3.68 (2H, dt), 7.72 (1H, dd), 8.00 (1H, d), 8.49 (1H, d), 8.98 (1H, s). Mass spectrum: m/z (ES+)[M+H]+ = 376.4.

[00477] The required 3H-imidazo[4,5-c]quinolin-2-one intermediates were prepared by cyclizing the appropriate intermediate acid as follows:Intermediate C2: 8-Bromo-7-fluoro-1-( cis -3 -methoxycyclobutyl)-3H-imidazo[4,5-c]quinolin-2-one

[00478] A solution of 6-bromo-7-fluoro-4-[(cis-3-methoxycyclobutyl)amino]quinoline-3-carboxylic acid (5.90 g, 15.98 mmol) and triethylamine (9.72 g , 96.06 mmol) in DMF (100 mL) was stirred at room temperature for 2 h, then diphenyl phosphorazidate (11.02 g, 40.04 mmol) was added. The resulting solution was stirred at 60°C for 2 hours before being concentrated in vacuo. The residue was diluted with water (80 mL) and the solids collected by filtration and dried in an oven under reduced pressure to provide the desired material (4.5 g, 77%) as a white solid. NMR spectrum: 1H NMR (300 MHz, CDCl3) δ 2.75 (2H, m), 2.95 (2H, m), 3.25 (3H, s), 3.85 (1H, m), 4 .75 (1H, m), 8.00 (1H, d), 8.62-8.58 (2H, t). Mass spectrum: m/z (ES+)[M+H]+ = 366.

[00479] The following 3H-imidazo[4,5-c]quinolin-2-one intermediates were similarly prepared from the appropriate carboxylic acid intermediates: * The reaction was stirred at 60°C for 1 hour.

[00480] Intermediate D2: NMR spectrum: 1H NMR (300 MHz, DMSO-d6) δ 1.84-2.11 (3H, m), 2.62-2.76 (1H, m), 3.35 -3.44 (1H, m), 3.92-4.22 (3H, m), 4.71-4.80 (1H, m), 7.76 (1H, dd), 7.98 (2H ,d), 8.32 (1H, dd), 8.71 (1H, s), 11.85 (1H, bs). Mass spectrum: m/z (ES+)[M+H]+ = 350.

[00481] Intermediate E2: NMR spectrum: 1H NMR (300 MHz, DMSO-d6) δ 1.82-2.11 (3H, m), 2.61-2.75 (1H, m), 3.34 -3.43 (1H, m), 3.91-4.21 (3H, m), 4.69-4.78 (1H, m), 7.75 (1H, dd), 7.99 (2H ,d), 8.33 (1H, dd), 8.69 (1H, s), 11.70 (1H, bs). Mass spectrum: m/z (ES+)[M+H]+ = 350.

[00482] Intermediate F2: NMR spectrum: 1H NMR (400 MHz, DMSO-d6, 100°C) δ 1.88 (2H, dd), 2.71 (2H, qd), 3.59 (2H, td ), 4.06 (2H, dd), 4.92 (1H, tt), 7.92 (1H, d), 8.57 (1H, d), 8.72 (1H, s), 11.43 (1H, s). Mass spectrum: m/z (ES+)[M+H]+ = 367.92.

[00483] Intermediate G2: NMR spectrum: 1H NMR (300 MHz, DMSO-d6) δ 5.01 (2H, t), 5.20 (2H, t), 6.08 (1H, m), 7, 96 (1H, d), 8.708.73 (1H, m), 8.74 (1H, s), 11.80 (1H, bs). Mass spectrum: m/z (ES+)[M+H]+ = 338.

[00484] Intermediate J2: NMR spectrum: 1H NMR (400 MHz, DMSO-d6) δ 2.70 - 2.76 (2H, m), 2.81 - 2.90 (2H, m), 4.04 -4.08 (1H, m), 4.75 (1H, p), 7.74 (1H, dd), 7.95 (1H, d), 8.45 (1H, d), 8.68 ( 1H, s), 11.62 (1H, s). Mass spectrum: m/z (ES+)[M+H]+ = 334, 336.

[00485] The acid intermediates were prepared from the intermediate ester as follows: Intermediate C3: 6-Bromo-7-fluoro-4-[( cis -3-methoxycyclobutyl)amino]quinoline-3-carboxylic acid

[00486] A solution of sodium hydroxide (8 g, 200 mmol) in water (100 mL) was added to a solution of 6-bromo-7-fluoro-4-[(cis-3-methoxycyclobutyl)amino]quinoline- Ethyl 3-carboxylate (6.0 g, 15.10 mmol) in MeOH (300 mL) and the resulting solution stirred overnight at room temperature. The temperature was increased to 40°C for another 2 hours. The pH value of the solution was adjusted to 5 with 1.5M hydrochloric acid and the solids collected by filtration and dried in an oven under reduced pressure to provide the desired material (5.6g) as a white solid which was used without purification. additional. NMR spectrum: 1H NMR (400 MHz, DMSO-d6) δ 1.98-1.91 (2H, m), 2.88-2.84 (2H, m), 3.17 (1H, s), 3.77-3.70 (1H, t), 4.22-4.19 (1H, t), 7.73 (1H, d), 8.44 (1H, d), 8.88 (1H, s), 13.27 (1H, s). Mass spectrum: m/z (ES+)[M+H]+ = 369.

[00487] Intermediate carboxylic acids were similarly prepared from the appropriate precursor ester: * The reaction was stirred at 60 - 70 °C for 1 - 3 hours. ** The reaction was stirred at room temperature overnight. 3 ** The reaction was carried out using a mixture of THF and water as the solvent and heated at 65°C for 3 hours.

[00488] Intermediate D3: NMR spectrum: 1H NMR (300 MHz, DMSO-d6) δ 1.50-1.57 (1H, m), 1.61 - 1.82 (2H, m), 1.98 - 2.13 (1H, m), 3.48-3.72 (3H, m), 3.89 (1H, d), 4.15-4.26 (1H, m), 7.77 (1H , dd), 7.95 (1H, d), 8.31(1H, d), 8.90 (1H,s), 13.38 (1H, bs). Mass spectrum: m/z (ES+)[M+H]+ = 351.

[00489] Intermediate E3: NMR spectrum: 1H NMR (300 MHz, DMSO-d6) δ 1.50-1.56 (1H, m), 1.62 - 1.83 (2H, m), 1.99 - 2.12 (1H, m), 3.50-3.71 (3H, m), 3.89 (1H, d), 4.16 -4.28 (1H, m), 7.78 (1H , dd), 7.94 (1H, d), 8.30(1H, d), 8.94 (1H,s), 13.50 (1H, bs). Mass spectrum: m/z (ES+)[M+H]+ = 351.

[00490] Intermediate F3: Mass spectrum: m/z (ES+)[M+H]+ =369.

[00491] Intermediate G3: Mass spectrum: m/z (ES+)[M+H]+ = 341.

[00492] Intermediate J3: NMR spectrum: 1H NMR (300 MHz, DMSO-d6) δ 2.03-2.07 (2H, m), 2.85-2.93 (2H, m), 4.00 -4.04 (1H, t), 4.21-4.35 (2H, m), 7.95 (1H, d), 8.16 (1H, dd), 8.58 (1H, s), 8.99 (1H, s), 11.02 (1H, s). Mass spectrum: m/z (ES+)[M+H]+ = 337, 339,

[00493] The above intermediate esters were prepared from the appropriate ethyl 4-chloroquinoline-3-carboxylate intermediates as follows:Intermediate C4:6-bromo-7-fluoro-4-[( cis -3-methoxycyclobutyl)amino]quinoline ethyl-3-carboxylate

[00494] A solution with ethyl 6-bromo-4-chloro-7-fluoroquinoline-3-carboxylate (7.5 g, 22.55 mmol), 3-methoxycyclobutan-1-amine hydrochloride (3.41 g, 24.78 mmol) and DIPEA (14.61 g, 113.04 mmol) in DMA (25 mL) was stirred at 85°C for 3 hours. The reaction mixture was cooled and the solids collected by filtration, washed with water (3 x 20 mL) and dried in an oven under reduced pressure to provide the desired material (6.9 g, 77%) as a white solid which was used without further purification. NMR spectrum: 1H NMR (400 MHz, CDCl3) δ 1.44-1.41 (3H, t), 2.21-2.14 (2H, m), 3.05-2.98 (2H, m ), 3.30 (3H, s), 3.94-3.75 (1H, m), 4.11-4.06 (1H, m), 4.43-4.37 (2H, d), 7.70 (1H, d), 8.29 (1H, d), 9.07 (1H, d), 9.69 (1H, s). Mass spectrum: m/z (ES+)[M+H]+ = 397.

[00495] The following intermediate esters were prepared analogously from the appropriate amine and ethyl 6-bromo-4-chloro-7-fluoroquinoline-3-carboxylate or ethyl 6-bromo-4-chloroquinoline-3-carboxylate : * The reaction was stirred at 80°C for 16 hours. ** The reaction was stirred at 90 °C for 1 - 3 hours.

[00496] Intermediate D4: NMR spectrum: 1H NMR (300 MHz, DMSO-d6) δ 1.36 (3H, t), 1.70-1.74 (1H, m), 1.75-1.77 (2H, m), 2.032.05 (1H, m), 3.58-3.61 (3H, m), 3.80-3.85 (1H, m), 4.01-4.03 (1H, m) , m), 4.35 (2H, q), 7.80 (1H, d), 7.89 (1H, dd), 8.58 (1H, s), 8.67 (1H, d), 8 .93 (1H, s). Mass spectrum: m/z (ES+)[M+H]+ = 380.8.

[00497] Intermediate E4: NMR spectrum: 1H NMR (400 MHz, DMSO-d6) δ 1.50 - 1.56(1H, m), 1.62 - 1.84 (2H, m), 1.99 - 2.13 (1H, m), 3.51 - 3.73 (3H, m), 3.89 (1H, d), 4.12 - 4.22 (1H, m), 7.77 (1H , d), 7.90 (1H, d), 8.31 (1H, s), 8.94 (1H, s), 13.41 (1H, s). Mass spectrum: m/z (ES+)[M+H]+ = 379.

[00498] Intermediate F4: Mass spectrum: m/z (ES+)[M+H]+ = 397.

[00499] Intermediate G4: Mass spectrum: m/z (ES+)[M+H]+ = 369.

[00500] Intermediate J4: NMR spectrum: 1H NMR (300 MHz, DMSO-d6) δ 1.35 (3H, t), 1.91-1.95 (2H, m), 2.77-2.81 (2H, m), 3.913.95 (2H, m), 4.35 (2H, q), 5.28 (1H, d), 7.78 (1H, d), 7.85 (1H, dd) , 8.37 (1H, d), 8.85 (1H, s), 8.89 (1H, d). Mass spectrum: m/z (ES+)[M+H]+ = 365, 367.

[00501] The preparation of ethyl 6-bromo-4-chloroquinoline-3-carboxylate has been described above. The preparation of ethyl 6-bromo-4-chloro-7-fluoroquinoline-3-carboxylate is described below: Intermediate C5: ethyl 6-bromo-4-chloro-7-fluoroquinoline-3-carboxylate

[00502] Thionyl chloride (150 mL, 2.08 mol) was added to a solution of ethyl 6-bromo-7-fluoro-4-oxo-1H-quinoline-3-carboxylate (25 g, 79.59 mmol ) in DMF (50 mL) and the solution stirred at 80°C for 4 hours. The mixture was concentrated under vacuum and quenched by the addition of ice/water. The reaction mixture was extracted with DCM (8 x 100 mL), the organic extracts combined and the mixture adjusted to pH = 7 by the addition of 1.5M ammonium hydrogen carbonate. The resulting mixture was washed with water (3 x 100 mL), the organic layers dried over Na 2 SO 4 and concentrated in vacuo to provide the desired material (20 g, 76%) as a pale yellow solid which was used without further purification. NMR spectrum: 1H NMR (400 MHz, CDCl3) δ 1.491.42 (3H, m), 4.54-4.82 (2H, q), 7.86 (1H, d), 8.69 (1H, d), 9.23 (1H, s). Mass spectrum: m/z (ES+)[M+H]+ = 334. Intermediate C6: Ethyl 6-bromo-7-fluoro-4-oxo-1H-quinoline-3-carboxylate

[00503] A solution of diethyl 2-[[(4-bromo-3-fluorophenyl)amino]methylidene]propanedioate (90 g, 249.88 mmol) in diphenyl ether (600 mL, 3.79 mol) was stirred at 240 °C for 2.5 hours. The mixture was allowed to cool to 70 °C, the solids collected by filtration and dried in a vacuum oven to provide the desired material (50 g, 64%) as a white solid which was used without further purification. NMR spectrum: 1H NMR (500 MHz, DMSO-d6, (100 °C)) δ 1.26 - 1.33 (3H, m), 4.25 (2H, q), 7.52 (1H, d ), 8.37 (1H, d), 8.48 (1H, s), 12.05 (1H, s). Mass spectrum: m/z (ES+)[M+H]+ = 314. Intermediate C7: Diethyl 2-[[(4-bromo-3-fluorophenyl)amino]methylidene]propanedioate

[00504] A solution of 4-bromo-3-fluoroaniline (56.6 g, 297.87 mmol) and 1,3-diethyl 2-(ethoxymethylidene)propanedioate (72.45 g, 335.06 mmol) in EtOH (560 mL) was stirred at 80°C for 4 hours. The reaction mixture was allowed to cool, the solids collected by filtration and dried in an oven to provide the desired material (90 g, 84%) as an off-white solid which was used without further purification. NMR spectrum: 1H NMR (400 MHz, DMSO-d6) δ 1.26 (6H, q), 4.14 (2H, q), 4.22 (2H, q), 7.18 - 7.25 ( 1H, m), 7.57 (1H, dd), 7.64 - 7.7 (1H, m), 8.33 (1H, d), 10.62 (1H, d). Mass spectrum: m/z (ES+)[M+H]+ = 360.

[00505] The necessary 3H-imidazo[4,5-c]quinolin-2-one intermediates were prepared by cyclization of the appropriate intermediate carboxamides as follows: Intermediate H2: 8-Bromo-1-(oxetan-3-yl)-3H -imidazo[4,5-c]quinolin-2-one

[00506] DBU (2.34 mL, 15.64 mmol) was added to 6-bromo-4-(oxetan-3-ylamino)quinoline-3-carboxamide (2.52 g, 7.82 mmol) and 1, 3,5-trichloro-1,3,5-triazinane-2,4,6-trione (0.727 g, 3.13 mmol) in MeOH (35 mL) and the resulting mixture stirred at room temperature overnight. The mixture was evaporated to dryness and the residue purified by FCC with gradient elution from 0 to 20% MeOH in DCM, giving the desired material (0.485g, 19.37%) as a cream solid. NMR spectrum: 1H NMR (400 MHz, DMSO-d6) δ 5.00 (2H, dd), 5.21 (2H, t), 5.87 - 6.15 (1H, m), 7.75 ( 1H, dd), 7.97 (1H, d), 8.51 (1H, d), 8.72 (1H, s), 11.73 (1H, s). Mass spectrum: m/z (ES+)[M+H]+ = 320, 322.

[00507] The following 3H-imidazo[4,5-c]quinolin-2-one intermediates were prepared analogously: * The reaction was stirred at room temperature for 70 hours, but it was still incomplete, so additional DBU and 1,3,5-trichloro-1,3,5-triazinane-2,4,6-trione were added, and the mixture was stirred at room temperature for a further 3 hours.

[00508] Intermediate K2: NMR spectrum: 1H NMR (400 MHz, DMSO-d6) δ 1.77 - 1.93 (2H, m), 2.10 (1H, d), 2.68 (1H, qd ), 3.34 - 3.44 (1H, m), 3.94 (1H, d), 4.08 (1H, dd), 4.18 (1H, t), 4.75 (1H, ddd) , 7.94 (1H, d), 8.48 (1H, d), 8.69 (1H, s), 11.63 (1H, s). Mass spectrum: m/z (ES+)[M+H]+ = 366, 368.

[00509] Intermediate L2: NMR spectrum: 1H NMR (400 MHz, DMSO-d6) δ 1.7 - 1.93 (2H, m), 2.10 (1H, d), 2.63 - 2.75 (1H, m), 3.49 - 3.61 (1H, m), 3.84 - 4.03 (1H, m), 4.08 (1H, dd), 4.19 (1H, t), 4.76 (1H, t), 7.95 (1H, d), 8.49 (1H, d), 8.70 (1H, s), 11.66 (1H, s), m/z: ES+ [M+H]+ 366, 368.

[00510] Suitable intermediate carboxamides were prepared as follows: Intermediate H3:6-Bromo-4-(oxetan-3-ylamino)quinoline-3-Carboxamide

[00511] Oxetan-3-amine (0.614 g, 8.41 mmol) was added to 6-bromo-4-chloroquinoline-3-carboxamide (2 g, 7.00 mmol) and DIPEA (2.440 mL, 14.01 mmol ) in DMA (24 mL) and the resulting mixture stirred at 100°C for 18 hours. The crude product was purified by ion exchange chromatography using an SCX column and eluting with 7M NH3/MeOH to provide the desired material (2.52 g, 112%) as a dark brown solid which was used without further purification. . NMR spectrum: 1H NMR (400 MHz, DMSO-d6) δ 4.06 - 4.15 (2H, m), 4.16 - 4.20 (2H, m), 5.63 - 5.96 (1H , m), 7.16 - 7.2 (3H, m), 7.22 - 7.26 (2H, m), 7.32 (1H, d), 7.93 (1H, d). Mass spectrum: m/z (ES+)[M+H]+ = 322, 324.

[00512] The following intermediates were prepared analogously from 6-bromo-4-chloro-7-fluoroquinoline-3-carboxamide: * The reaction was stirred at 80 °C overnight.

[00513] Intermediate K3: NMR spectrum: 1H NMR (400 MHz, DMSO-d6) δ 1.52 (1H, td), 1.59 - 1.79 (2H, m), 2.02 (1H, d ), 3.32 - 3.48 (2H, m), 3.68 (1H, dd), 3.87 (1H, dd), 3.9 - 4.01 (1H, m), 7.56 ( 1H, s), 7.71 (1H, d), 8.10 (1H, s), 8.20 (1H, d), 8.62 (2H, d). Mass spectrum: m/z (ES-)[M-H]- = 366.

[00514] Intermediate L3: NMR spectrum: 1H NMR (400 MHz, DMSO-d6) δ 1.52 (1H, td), 1.67 (2H, ddd), 2.02 (1H, d), 3, 32 - 3.5 (2H, m), 3.68 (1H, dd), 3.87 (1H, dd), 3.91 - 4.02 (1H, m), 7.56 (1H, s) , 7.71 (1H, d), 8.10 (1H, s), 8.20 (1H, d), 8.62 (2H, d). Mass spectrum: m/z (ES+)[M+H]+ = 368, 370.

[00515] The preparation of 6-bromo-4-chloroquinoline-3-carboxamide has been described above. The preparation of 6-bromo-4-chloro-7-fluoroquinoline-3-carboxamide is described below. Intermediate K4: 6-Bromo-4-chloro-7-fluoroquinoline-3-carboxamide

[00516] DMF (0.5 mL) was added to a stirred suspension of 6-bromo-7-fluoro-4-oxo-1H-quinoline-3-carboxylic acid (22.5 g, 78.66 mmol) in chloride of thionyl (140 g, 1179.85 mmol) and the mixture heated at reflux for 2 hours. The reaction was allowed to cool, concentrated in vacuo and the residue azeotroped twice with toluene to give a yellow solid. This solid was added portionwise to an ammonium hydroxide solution (147 mL, 1179.85 mmol) at 0 °C. The white suspension was stirred for 15 minutes, then the solid was filtered, washed with water and dried under vacuum to provide the desired material (23.80 g, 100%) as a white powder. NMR spectrum: 1H NMR (400 MHz, DMSO-d6) δ 8.92 (1H, s), 8.59 (1H, d), 8.21 (1H, s), 8.09 (1H, d) , 7.98 (1H, s). Mass spectrum: m/z (ES+)[M+H]+ = 304.8. Intermediate K5: 6-Bromo-7-fluoro-4-oxo-1H-quinoline-3-carboxylic acid

[00517] A solution of sodium hydroxide (18.34 g, 458.44 mmol) in water (100 mL) was added to a stirred suspension of 6-bromo-7-fluoro-4-oxo-1H-quinoline-3 ethyl -carboxylate (28.8 g, 91.69 mmol) in EtOH (500 mL) at room temperature. The reaction mixture was then stirred at 75 °C for 2 hours, allowed to cool and adjusted to pH 4 using 2N hydrochloric acid. The precipitate was collected by filtration, washed with water and dried under vacuum to provide the desired material (23.30 g, 89%) as a white powder. NMR spectrum: 1H NMR (400 MHz, DMSO-d6) δ 14.78 (1H, s), 13.45 (1H, s), 8.93 (1H, s), 8.46 (1H, d) , 7.70 (1H, d). Mass spectrum: m/z (ES+)[M+H]+ = 287.8.

[00518] The preparation of ethyl 6-bromo-7-fluoro-4-oxo-1H-quinoline-3-carboxylate has already been described.

[00519] The required 3H-imidazo[4,5-c]quinolin-2-one intermediates were prepared by cyclization of the appropriate amino intermediates as follows:Intermediate I2: 8-Bromo-7-fluoro-1-(4-methyloxan- 4-yl)-3H-imidazo[4,5-c]quinolin-2-one

[00520] 6-Bromo-7-fluoro-N'-(4-methyloxan-4-yl)quinoline-3,4-diamine (1.1 g, 3.11 mmol) was added to bis(trichloromethyl)carbonate ( 0.553 g, 1.86 mmol) in DCM (20 mL) and the resulting mixture stirred at 30°C for 2 hours. The crude product was purified by FCC, gradient elution from 0 to 5% MeOH in DCM, providing the desired material (0.950 g, 80%) as a brown solid which was used without further purification.

[00521] The following intermediate was prepared analogously from the appropriate precursor: * Triethylamine (1.2 equivalents) was added to a reaction mixture and the reaction proceeded at room temperature for 2 hours. The reaction mixture was purified using an SCX column, the desired material being eluted with 7M ammonia in MeOH. Intermediate M2: Mass spectrum: m/z (ES-)[MH]- = 362.39.

[00522] The preparation of suitable amino intermediates is described below: Intermediate I3: 6-Bromo-7-fluoro-N '-(4-methyloxan-4-yl)quinoline-3,4-diamine

[00523] 6-Bromo-7-fluoro-N-(4-methyloxan-4-yl)-3-nitroquinolin-4-amine (1.215 g, 3.16 mmol) was added to iron powder (1.8 g ) in acid (15 mL). The mixture was stirred and gently heated with a hot air gun (approximately 60 °C) to start the reaction. The heat source was removed and the resulting mixture was stirred for 1 hour. The reaction mixture was diluted with water and the solids filtered off and discarded. The filtrate was concentrated in vacuo, diluted with water and extracted with EtOAc. The organic phases were dried over Na2SO4 and concentrated in vacuo to provide the desired material (1.10 g, 98%) as a brown solid which was used without further purification. Intermediate I4: 6-Bromo-7-fluoro-N-(4-methyloxan-4-yl)-3-nitroquinolin-4-amine

[00524] 6-Bromo-4-chloro-7-fluoro-3-nitroquinoline (1 g, 3.27 mmol) was added to a solution of 4-methyltetrahydro-2H-pyran-4-amine hydrochloride (0.596 g, 3.93 mmol) and DIPEA (1.715 mL, 9.82 mmol) in DMA (10 mL) and the resulting mixture stirred at 100°C for 4 hours. The reaction mixture was diluted with water and the solid collected by filtration and dried to provide the desired material (1.215 g, 97%) as a brown solid which was used without further purification.

[00525] The synthesis of 6-bromo-4-chloro-7-fluoro-3-nitroquinoline has been reported in the literature (eg Garcia-Echeverria, C. et al., WO2006122806), which is available as a reagent (e.g., Aces Pharma, Inc - order number 74244).

[00526] 6-Bromo-N'-(4-methyloxan-4-yl)quinoline-3,4-diamine was prepared as follows: Intermediate M3: 6-Bromo-N'-(4-methyloxan-4-yl) )quinoline-3,4-diamine

[00527] Water (8.35 mL) was added to a stirred mixture of 6-bromo-N-(4-methyloxan-4-yl)-3-nitroquinolin-4-amine (1.07 g, 2.92 mmol ), iron (0.979 g, 17.53 mmol) and ammonium hydrochloride (0.109 g, 2.05 mmol) in EtOH (50.1 mL) and the resulting slurry heated to 105°C for 2 hours. The reaction was filtered warm through a pad of celite, washed with MeOH and the filtrate evaporated until completely dry. The crude solid was dissolved in DCM (10 mL) and washed with saturated aqueous NaHCO 3 solution (10 mL) and saturated brine (10 mL). The organic layer was dried with MgSO 4 , filtered and evaporated to give the desired material (0.850 g, 87%) as a light orange solid. This solid was used without further purification. NMR spectrum: 1H NMR (400 MHz, DMSO-d6) δ 1.19 (3H, s), 1.51 (2H, d), 1.76 (2H, td), 3.43 (2H, td) , 3.73 (2H, dt), 4.15 (1H, s), 5.45 (2H, s), 7.39 (1H, dd), 7.67 (1H, d), 8.22 ( 1H, d), 8.51 (1H, s). Mass spectrum: m/z (ES+)[M+H]+ = 336, 338. Intermediate M4: 6-Bromo-N-(4-methyloxan-4-yl)-3-nitroquinolin-4-amine

[00528] A solution of 6-bromo-4-chloro-3-nitroquinoline (1 g, 3.48 mmol), 4-methyltetrahydro-2H-pyran-4-amine hydrochloride (1.055 g, 6.96 mmol ) and triethylamine (1.939 mL, 13.91 mmol) in DMF (10 mL) was heated to 100 °C for 1 hour in a closed tube in the microwave reactor. The mixture was allowed to cool then poured into stirred water (50ml) and the resulting yellow precipitate was collected by filtration and dried under vacuum to provide the desired material (1.070g, 84%) as a yellow solid. This solid was used without further purification. NMR spectrum: 1H NMR (400 MHz, DMSO-d6) δ 1.40 (3H, s), 1.78 (2H, dt), 1.89 (2H, ddd), 3.51 - 3.64 ( 4H, m), 7.80 (1H, s), 7.91 (1H, d), 8.01 (1H, dd), 8.48 (1H, d), 9.18 (1H, s). Mass spectrum: m/z (ES+)[M+H]+ = 366, 368.

[00529] The synthesis of 6-bromo-4-chloro-3-nitroquinoline has been reported in the literature (eg Garcia-Echeverria, C. et al., WO2005054238), and this is available as a commercial reagent (p. g., Aces Pharma, Inc - order number 74381).

[00530] Intermediate N1, tert-butyl 8-bromo-1-(oxan-4-yl)-2-oxoimidazo[5,4-c]quinoline-3-carboxylate, used to prepare Example 13 was prepared as described below: Intermediate N1: tert-butyl 8-bromo-1-(oxan-4-yl)-2-oxoimidazo[5,4-c]quinoline-3-carboxylate

[00531] Di-tert-butyl dicarbonate (376mg, 1.72 mmol) was added to a mixture of 8-bromo-1-(oxan-4-yl)-3H-imidazo[4,5-c]quinolin- 2-one (300 mg, 0.86 mmol) and triethylamine (0.240 mL, 1.72 mmol) in DCM (20 mL). The resulting solution was stirred at room temperature for 4 hours, then concentrated in vacuo. The crude product was purified by FCC, gradient elution from 0 MeOH to 60% MeOH in DCM, providing the desired material (310 mg, 80%) as a white solid. NMR spectrum: 1H NMR (300 MHz, CDCl3) δ 1.72 (9H, s), 1.81-1.95 (2H, m), 2.92-3.03 (2H, m), 3, 57-3.65 (2H, m), 4.26 (2H, dd), 4.89-4.94 (1H, m), 7.82 (1H d), 8.32-8.35 (1H , m), 8.39 (1H, s), 9.49 (1H, m). Mass spectrum: m/z (ES+)[M+H]+ = 448.

[00532] 2-[3-(Azetidin-1-yl)propoxy]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine, 2-(3- pyrrolidin-1-ylpropoxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine and 3-[6-fluoro-5-(4,4,5, 5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl]oxy-N,N-dimethylpropan-1-amine were prepared as follows: 2-[3-(Azetidin-1-yl) propoxy]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine

[00533] n-Butyllithium (4.65 mL, 11.62 mmol) was added to 2-[3-(azetidin-1-yl)propoxy]-5-bromopyridine (2.1 g, 7.74 mmol ) and 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.161 g, 11.62 mmol) in THF (50 mL) at -78 °C over a period of 10 minutes and the resulting solution stirred at -78 °C for 1 hour. The reaction was quenched with saturated Na2SO4 (10 mL) and the solvent removed in vacuo. The residue was dissolved in DCM (100ml), dried over Na 2 SO 4 , filtered and evaporated to give the desired material (2.00g, 81%) as a white solid. Mass spectrum: m/z (ES+)[M+H]+ = 319. 2-[3-(Azetidin-1-yl)propoxy]-5-bromopyridine

[00534] Sodium hydride (1.364 g, 56.82 mmol) was added to 3-(azetidin-1-yl)propan-1-ol (2.62 g, 22.73 mmol) in THF (20 mL) at room temperature under an inert atmosphere and the reaction stirred for 10 minutes. 5-Bromo-2-fluoropyridine (2.0 g, 11.36 mmol) was added and the resulting solution stirred for 1 hour before quenching with water (20 mL) and extracted with EtOAc (5 x 50 mL). The organic phases were combined, dried over Na 2 SO 4 , filtered and concentrated in vacuo to provide the desired material (3.75 g, 122%) as a white solid. NMR spectrum: 1H NMR (300 MHz, CDCl3) δ 1.80 (2H, m), 2.11 (2H, m), 2.55 (2H, t), 3.18 (4H, t), 4.328 (2H, t), 6.64 (1H, d), 7.62 (1H, dd), 8.16 (1H, d). Mass spectrum: m/z (ES+)[M+H]+ = 271.3-(Azetidin-1-yl)propan-1-ol

[00535] A solution of lithium aluminum hydride (2.0 M in THF) (8.38 mL, 16.76 mmol), diluted in more THF (20 mL), was added to a mixture of 3-(azetidin Methyl-1-yl)propanoate (2 g, 13.97 mmol) in THF (5 mL) dropwise at 0 °C under an inert atmosphere. The resulting solution was stirred at 0 °C for 1 hour, then the reaction mixture was treated with sodium sulfate decahydrate and stirred for 30 minutes. The solid was filtered off and discarded and the filtrate evaporated to give the desired material (1.240 g, 77%) as a colorless oil. NMR spectrum: 1H NMR (400 MHz, CDCl3) δ 1.51 - 1.57 (2H, m), 2 - 2.07 (2H, m), 2.6 - 2.66 (2H, m), 3.20 (4H, t), 3.7 - 3.76 (2H, m). Methyl 3-(Azetidin-1-yl)propanoate

[00536] Methyl acrylate (2.082 mL, 23.12 mmol) was added to a solution of azetidine (1.2 g, 21.02 mmol) in DCM and the resulting solution stirred at room temperature under an inert atmosphere for 16 hours . The reaction mixture was evaporated and the crude product purified by FCC, eluted with 25% EtOAc in DCM, to give the desired material (2.0g, 66.5%) as a colorless oil. NMR spectrum: 1H NMR (400 MHz, CDCl3) δ 1.97 - 2.1 (2H, m), 2.33 (2H, d), 2.67 (2H, d), 3.18 (4H, d). t), 3.67 (3H, s). 2-(3-Pyrrolidin-1-ylpropoxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine

[00537] n-Butyllithium (5.68 mL, 14.20 mmol) was added dropwise to the mixture of 5-bromo-2-(3-pyrrolidin-1-ylpropoxy)pyridine (2.7 g, 9 .47 mmol) and 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.64 g, 14.20 mmol) in THF (20 mL) at -78 °C over over a period of 10 minutes under an inert atmosphere. The resulting mixture was allowed to warm to room temperature and stirred for 12 hours. The reaction mixture was quenched by the addition of a saturated aqueous ammonium chloride solution, extracted with EtOAc (2 x 50 mL) and the organic layer dried with Na 2 SO 4 , filtered and evaporated to give the desired material (3.10 g , 99%) as a yellow oil. The product was used in the next step directly without further purification. NMR spectrum: 1H NMR (400 MHz, CDCl3) δ 1.26-1.41(12H, m),1.77-1.80 (4H, m), 1.95-2.04(2H , m), 2.50-2.58 (4H, m), 2.62 (2H, t), 4.37 (2H, t), 6.69 (1H, d), 7.91 (1H, t). d), 8.52 (1H, s). Mass spectrum: m/z (ES+)[M+H]+ = 251,5-bromo-2-(3-pyrrolidin-1-ylpropoxy)pyridine

[00538] Sodium hydride (0.591 g, 14.77 mmol) was added portionwise to a solution of 3-(pyrrolidin-1-yl)propan-1-ol (1.615 g, 12.50 mmol) in THF (20 mL) at 0 °C then stirred at room temperature for 30 minutes. 5-Bromo-2-fluoropyridine (2 g, 11.36 mmol) was added and the resulting mixture stirred at room temperature for 2 hours before being quenched by the addition of a saturated aqueous ammonium chloride solution. Moisture was extracted with EtOAc (2 x 100 mL) and the organic layer dried with Na 2 SO 4 , filtered and evaporated to give a pale yellow solid. The crude product was purified by FCC, gradient elution from 0 to 10% MeOH in DCM, providing the desired material (2.70 g, 83%) as a yellow solid. Mass spectrum: m/z (ES+)[M+H]+ = 285.3-[6-Fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin -2-yl]oxy-N,N-dimethylpropan-1-amine

[00539] A solution of n-butyllithium (0.693 g, 10.83 mmol) in n-hexane (4.33 mL) was added to a stirred mixture of 3-(5-bromo-6-fluoropyridin-2-yl) oxy-N,N-dimethylpropan-1-amine (2 g, 7.22 mmol) and 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.014 g, 10.83 mmol ) in THF (20 mL) at -78 °C over a period of 20 minutes under an inert atmosphere. The resulting mixture was allowed to warm to room temperature and stirred for 2 hours. The reaction mixture was quenched with saturated NaHCO 3 solution and concentrated in vacuo. The crude product was purified by FCC, gradient elution from 0 to 10% MeOH in DCM, providing the desired material (2.50 g, 107%). Mass spectrum: m/z (ES+)[M+H]+ = 325.3-(5-Bromo-6-fluoropyridin-2-yl)oxy-N,N-dimethylpropan-1-amine

[00540] (E)-Diisopropyl diazene-1,2-dicarboxylate (15.80 g, 78.13 mmol) was added dropwise to 3-(dimethylamino)propan-1-ol (8.06 g, 78 .13 mmol), 5-bromo-6-fluoropyridin-2-ol (10 g, 52.09 mmol) and triphenylphosphine (20.49 g, 78.13 mmol) in DCM (150 mL) and cooled to 0-5 °C °C under an inert atmosphere. The resulting solution was stirred at room temperature for 16 hours, then the solvent was removed under reduced pressure. The residue was diluted with EtOAc (50 mL) and the solid filtered off and discarded. The filtrate was acidified with hydrogen chloride in dioxane. The solid was collected by filtration then dissolved in a saturated aqueous Na 2 CO 3 solution (200 mL) and extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with water, brine, dried over Na 2 SO 4 and concentrated in vacuo to provide the desired material (9.00 g, 62.3%). NMR spectrum: 1H NMR (300 MHz, CDCl3) δ 1.89 - 1.98 (2H, m), 2.26 (6H, s), 2.34 (2H, t), 4.30 (2H, t), 6.53 (1H, d), 7.74 (1H, t). Mass spectrum: m/z (ES+)[M+H]+ = 277.5-Bromo-6-fluoropyridin-2-ol

[00541] A solution of sodium nitrite (21.67 g, 314.13 mmol) in water (150 mL) was added dropwise to a stirred mixture of 5-bromo-6-fluoropyridin-2-amine (50 g , 261.78 mmol) and sulfuric acid (1.2 mL, 22.51 mmol) in water (750 mL) at 0-5 °C. The resulting suspension was stirred for 48 hours at room temperature, then the precipitate was collected by filtration, washed with water (200 mL) and dried under vacuum to provide the desired material (40.0 g, 80%) as a solid. light yellow, which was used without further purification. NMR spectrum: 1H NMR (300 MHz, DMSO-d6) δ 6.55 (1H, d), 8.00 (1H, t), 11.71 (1H, bs). Mass spectrum: m/z (ES+)[M+H]+ = 192.5-bromo-6-fluoropyridin-2-amine

[00542] NBS (50.0 g, 280.99 mmol) was added slowly to 6-fluoropyridin-2-amine (30 g, 267.61 mmol) in MeCN (300 mL) and cooled to 10-20 °C at over a period of 30 minutes. The resulting solution was stirred at room temperature for 60 minutes, then the solvent was removed under reduced pressure. The residue was diluted with water, the precipitate collected by filtration, washed with water (200 mL) and dried under vacuum to provide the desired material (50.0 g, 98%) as a white solid, which was used without further purification. NMR spectrum: 1H NMR (300 MHz, DMSO-d6) δ 6.29 (1H, d), 6.57 (2H, bs), 7.65 (1H, t). Mass spectrum: m/z (ES+)[M+H]+ = 191. Examples 25 and 26 8-[6-(3-dimethylaminopropoxy)pyridin-3-yl]-1-[(1 R ,3 R ) -3-methoxycyclopentyl]-3-methylimidazo[4,5-c]quinolin-2-one and 8-[6-(3-dimethylaminopropoxy)pyridin-3-yl]-1-[(1 S ,3 S )- 3-methoxycyclopentyl]-3-methylimidazo[4,5-c]quinolin-2-one

[00543] Chloro(2-dicyclohexylphosphine-2',4',6'-triisopropyl-1,1-biphenyl)[2-(2-amino-1,1'-biphenyl)]palladium (II) (26 .1mg, 0.03mmol) was added to 8-bromo-1-[(1R,3R)-3-methoxycyclopentyl]-3-methylimidazo[4,5-c]quinolin-2-one:8-bromo-1 -[(1S,3S)-3-methoxycyclopentyl]-3-methylimidazo[4,5-c]quinolin-2-one (1:1 mixture) (250 mg, 0.66 mmol), N,N-dimethyl- 3-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl]oxypropan-1-amine (244 mg, 0.80 mmol) and Cs2CO3 (433 mg, 1.33 mmol) in 1,4-dioxane (20 mL) and water (5 mL) and the resulting mixture stirred at 100 °C for 2 hours. The reaction mixture was poured into water (25ml), extracted with DCM (2x50ml), the organic layer dried over Na 2 SO 4 , filtered and evaporated to give a yellow residue. The crude product was purified by preparative HPLC (XSelect CSH Prep C18 OBD column, 5μ silica, 19 mm diameter, 150 mm length), using mixtures of water of decreasing polarity (containing 0.1% formic acid) and MeCN as eluents . Fractions containing the desired compound were evaporated to dryness to give the desired material in racemic mixture (175 mg, 53.3%) as a white solid. Optimization on the Agilent 1100, AD column, (20 micron silica, 4.6 mm diameter, 250 mm length) showed that MeCN/MeOH/TEA, 95/05/0.1 would provide the best separation. This method was used for preparative HPLC purification. The racemic mixture (130 mg, 0.27 mmol) was dissolved in EtOH (10 mL) and separated with preparative HPLC on an AD column (20 µm silica, 50 mm diameter, 250 mm length), requiring two injections to prepare the entire sample. The mixed fractions were subjected to a second separation using the above method, and the fractions containing the desired pure enantiomers were evaporated to provide the desired materials. This method provided mixed fractions that were further purified using the same conditions. The fractions containing the separated isomers were evaporated until completely dry.

[00544] Example 25: Isomer 1 (58 mg)

[00545] NMR spectrum: 1H NMR (400 MHz, CDCl3) δ 1.87 - 1.98 (1H, m), 2.04 (3H, dt), 2.33 (8H, s), 2.47 - 2.64 (3H, m), 2.72 (1H, ddd), 3.36 (3H, s), 3.59 (3H, s), 4.09 - 4.21 (1H, m), 4.43 (2H, t), 5.59 (1H, q), 6.88 (1H, d), 7.80 (1H, dd), 7.92 (1H, dd), 8.22 (1H , d), 8.33 (1H, d), 8.50 (1H, d), 8.70 (1H, s). Mass spectrum: m/z (ES+)[M+H]+ = 476.

[00546] Example 26: Isomer 2 (58 mg)

[00547] NMR spectrum: 1H NMR (400 MHz, CDCl3) δ 1.94 (1H, m), 1.99 - 2.11 (3H, m), 2.32 (8H, s), 2.46 - 2.64 (3H, m), 2.66 - 2.83 (2H, m), 3.36 (3H, s), 3.59 (3H, s), 4.17 (1H, m), 4.43 (2H, t), 5.44 - 5.72 (1H, m), 6.88 (1H, d), 7.80 (1H, dd), 7.91 (1H, dd), 8 .22 (1H, d), 8.33 (1H, d), 8.50 (1H, d), 8.70 (1H, s). Mass spectrum: m/z (ES+)[M+H]+ = 476.

[00548] The preparation of 8-bromo-1-[(1R,3R)-3-methoxycyclopentyl]-3-methylimidazo[4,5-c]quinolin-2-one:8-bromo-1-[(1S, 3S)-3-methoxycyclopentyl]-3-methylimidazo[4,5-c]quinolin-2-one (1:1 mixture) is described below: Intermediate O1:8-Bromo-1-[(1R ,3R ) -3-methoxycyclopentyl]-3-methylimidazo[4,5-c]quinolin-2-one:8-bromo-1-[(1 S ,3 S )-3-methoxycyclopentyl]-3-methylimidazo[4,5- c]quinolin-2-one (1:1 mixture)

[00549] A mixture of 6-bromo-4-[[(1R,3R)-3-methoxycyclopentyl]amino]quinoline-3-carboxylic acid: 6-bromo-4-[[(1S,3S)-3- methoxycyclopentyl]amino]quinoline-3-carboxylic acid (1:1 mixture) (13 g, 35.8 mmol), tetrabutylammonium bromide (1.16 g, 3.60 mmol), iodomethane (7.645 g, 53.86 mmol) and sodium hydroxide (2.15 g, 53.75 mmol) in DCM (600 mL) and water (380 mL) was stirred at room temperature overnight. The resulting solution was concentrated under vacuum to remove organic phases, and the solids were collected by filtration, washed with water (5x10 mL) and dried in a vacuum oven to provide the desired material (racemic mixture) (9.8 g, 73%) as an off-white solid. NMR spectrum: 1H NMR (400 MHz, DMSO-d6) δ 1.81-1.87 (1H, m), 2.33-2.51 (4H, m), 2.45-2.51 (1H , m), 3.28 (3H, s), 3.49 (3H, s), 4.02-4.21 (1H, m), 5.40 (1H, p), 7.73 (1H, dd), 7.98 (1H, d), 8.35 (1H, d), 8.91 (1H, s). Mass spectrum: m/z (ES+)[M+H]+ = 375.9. Intermediate O2: 8-bromo-1-[(1 R ,3 R )-3-methoxycyclopentyl]-3H-imidazo[4,5-c]quinolin-2-one:8-bromo-1-[(1 S , 3S)-3-methoxycyclopentyl]-3H-imidazo[4,5-c]quinolin-2-one (1:1 mixture)

[00550] A mixture of 6-bromo-4-[[(1R,3R)-3-methoxycyclopentyl]amino]quinoline-3-carboxylic acid: 6-bromo-4-[[(1S,3S)-3- methoxycyclopentyl]amino]quinoline-3-carboxylic acid (1:1 mixture) (17 g, 46.54 mmol), triethylamine (14.1 g, 139.34 mmol) in DMF (270 mL) was stirred at room temperature for 1 hour. Diphenyl phosphorazidate (25.6 g, 93.02 mmol) was added dropwise with stirring, and the solution was stirred at room temperature for a further 20 minutes before being heated to 60 °C for 1 hour. The reaction was allowed to cool and concentrated under vacuum. The residue was diluted with water (300 mL), the solids collected by filtration and dried in an oven under reduced pressure to provide the desired material (in racemic mixture) (13 g, 77%) as an off-white solid. Mass spectrum: m/z (ES+)[M+H]+ = 362.2. Intermediate O3: 6-bromo-4-[[(1 R ,3 R )-3-methoxycyclopentyl]amino]quinoline-3 acid -carboxylic acid: 6-bromo-4-[[(1S ,3 S )-3-methoxycyclopentyl]amino]quinoline-3-carboxylic acid (mixture 11)

[00551] 2N Sodium hydroxide (150 mL) was added to a mixture of ethyl 6-bromo-4-[[(1R,3R)-3-methoxycyclopentyl]amino]quinoline-3-carboxylate:6-bromo-4 Ethyl-[[(1S,3S)-3-methoxycyclopentyl]amino]quinoline-3-carboxylate (1:1 mixture) (18.6 g, 47.2 mmol) in MeOH (500 mL) and water (100 mL ) and the resulting solution stirred for 15 hours at room temperature. The mixture was concentrated in vacuo and the residue diluted with water (300 mL). The pH value of the solution was adjusted to 5 with 2N hydrochloric acid, the solids collected by filtration and dried in an oven under reduced pressure to give the desired material (in racemic mixture) (17.1g) as an off-white solid. NMR spectrum: 1H NMR (400 MHz, DMSO-d6) δ 1.60-1.71 (2H, m), 1.81-1.88 (1H, m), 1.96-2.02 (1H , m), 2.03-2.10 (2H, m), 3.21 (3H, s), 3.91-3.96 (1H, m), 4.51-4.72 (1H, m ), 7.77 (1H, d), 7.93 (1H, d), 8.45 (1H, d), 8.85 (1H, s), 13.30 (1H, bs). Mass spectrum: m/z (ES+)[M+H]+ = 365.2. Ethyl O4:6-bromo-4-[[(1 R ,3 R )-3-methoxycyclopentyl]amino]quinoline-3-carboxylate:6-bromo-4-[[(1S ,3 S )-3- Ethyl methoxycyclopentyl]amino]quinoline-3-carboxylate (1:1 mixture)

[00552] A mixture of ethyl 6-bromo-4-chloroquinoline-3-carboxylate (15 g, 47.69 mmol), (trans)-3-methoxycyclopentan-1-amine (racemic mixture) (8.09 g, 26.68 mmol) and DIPEA (19.68 g, 152.27 mmol) in DMA (100 mL) was stirred at 80 °C for 4 hours under an inert atmosphere. The reaction was stopped by the addition of water (500 mL) and the solids were collected by filtration and dried in an oven under reduced pressure to provide the desired material (in racemic mixture) (18.6 g) as a light brown solid. Mass spectrum: m/z (ES+)[M+H]+ = 393, 395.

[00553] The preparation of ethyl 6-bromo-4-chloroquinoline-3-carboxylate has been described above. Example 27 7-Fluoro-1-( cis -3-methoxycyclobutyl)-3-methyl-8-[6-(3-pyrrolidin-1-ylpropoxy)pyridin-3-yl]imidazo[4,5-c]quinolin- 2-one

[00554] 3-(Pyrrolidin-1-yl)propan-1-ol (46.9mg, 0.36 mmol) was added to sodium hydride (29.1mg, 1.21 mmol) in THF (4 mL) at room temperature over a period of 20 minutes. 7-Fluoro-8-(6-fluoropyridin-3-yl)-1-(cis-3-methoxycyclobutyl)-3-methylimidazo[4,5-c]quinolin-2-one (120 mg, 0.30 mmol) was added. The resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was quenched with water and the crude product purified by FCC with gradient elution from 0 to 5% MeOH in DCM. The crude product was purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 19 mm diameter, 100 mm length) using mixtures of decreasing polarity water (containing 0.1% formic acid) and MeCN as eluents . Fractions containing the desired compound were evaporated to dryness to provide the desired material (60.0 mg, 38.7%) as an off-white solid. NMR spectrum: 1H NMR (300 MHz, MeOD) δ 1.902.00 (4H, m), 2.10-2.20 (2H, m), 2.81-3.00 (8H, m), 3, 04-3.17 (2H, m), 3.28 (3H, s), 3.6 (3H, s), 3.85-3.96 (1H, m), 4.48 (2H, t) , 5.00-5.13 (1H, m), 6.88 (1H, d), 7.82 (1H, d), 8.05 (1H, d), 8.43-8.50 (2H , m), 8.83 (1H, s). Mass spectrum: m/z (ES+)[M+H]+ = 506.

[00555] The following compounds were prepared analogously using the appropriate alcohol and the appropriate pyridyl-fluoro intermediate. * The reaction was carried out in DMF between 0 °C and room temperature. ** The reaction was performed in DMA at 50 °C.

[00556] Example 28: NMR spectrum: 1H NMR (400 MHz, DMSOd6) δ 1.67-1.96 (6H, m), 2.44-2.55 (6H, m), 2.78-3 .03 (4H, m), 3.19 (3H, s), 3.50 (3H, s), 3.84-3.88 (1H, m), 4.38 (2H, t), 5, 13 (1H, p), 6.97 (1H, d), 7.92 (1H, dd), 8.12 (1H, dd), 8.20 (1H, dd), 8.43 (1H, s ), 8.67 (1H, d), 8.88 (1H, s). Mass spectrum: m/z (ES+)[M+H]+ = 488.

[00557] Example 29: NMR spectrum: 1H NMR (300 MHz, DMSOd6) δ 1.68 - 1.86 (6H, m), 1.95 (2H, p), 2.10-2.19 (1H , d), 2.51 - 2.75 (7H, m), 3.35 - 3.49 (1H, m), 3.50 (3H, s), 3.92 (1H, d), 4, 08-4.18 (1H, m), 4.22 (1H, t), 4.38 (2H, t), 4.90-5.03 (1H, m), 6.98 (1H, d) , 7.92 (1H, dd), 8.15-8.20 (1H, m), 8.25 (1H, s), 8.32 (1H, s), 8.66 (1H, d), 8.90 (1H, s). Mass spectrum: m/z (ES+)[M+H]+ = 488.

[00558] Example 30: NMR spectrum: 1H NMR (400 MHz, DMSOd6) δ 1.67-1.73 (4H, m), 1.90-1.98 (4H, m), 2.39-2 .46 (4H, m), 2.54-2.61 (2H, m), 2.72 (2H, ddd), 3.52 (3H, s), 3.59 (2H, t), 4, 06 (2H, dd), 4.38 (2H, t), 5.13-5.16 (1H, m), 6.98 (1H, d), 7.96 (1H, dd), 8.14 (1H, d), 8.20 (1H, dd), 8.45 (1H, s), 8.67 (1H, d), 8.91 (1H, s). Mass spectrum: m/z (ES+)[M+H]+ = 488.

[00559] Example 31: NMR spectrum: 1H NMR (300 MHz, DMSOd6) δ 1.38-1.50 (6H, m), 1.83-1.95 (4H, m), 2.13-2 .18 (1H, m), 2.35-2.43 (6H, m), 2.62-2.75 (1H, m), 3.38-3.44 (1H, m), 3.49 (3H, s), 3.94 (1H, d), 4.13-4.27 (2H, m), 4.35 (2H, t), 4.90-5.02 (1H, m), 6.99 (1H, d), 7.94 (1H, d), 8.13-8.18 (2H, m), 8.34 (1H, s), 8.48 (1H, d), 8 .90 (1H, s). Mass spectrum: m/z (ES+)[M+H]+ = 502.

[00560] Example 32: NMR spectrum: 1H NMR (300 MHz, DMSO-d6) δ 1.35-1.58 (6H, m), 1.85-1.98 (4H, m), 2.12 -2.21 (1H, m), 2.212.50 (6H, m), 2.60-2.80 (1H, m), 3.33-3.48 (1H, m), 3.48 (3H , s), 3.893.97 (1H, m), 4.10-4.28 (2H, m), 4.30-4.38 (2H, m), 4.90-5.08 (1H, m ), 6.98 (1H, d), 7.93-8.0 (1H, m), 8.13-8.22 (2H, m), 8.35 (1H, s), 8.63 ( 1H, s), 8.94 (1H, s). Mass spectrum: m/z (ES+)[M+H]+ = 502.3.

[00561] Example 33: NMR spectrum: 1H NMR (300 MHz, DMSO-d6) δ 1.32-1.45 (2H, m), 1.45-1.51 (4H, m), 1.88 -1.98 (2H, m), 2.312.51 (6H, m), 2.81-2.83(2H, m), 2.97-3.11 (2H, m), 3.19 (3H , s), 3.50 (3H, s), 3.84-3.91 (1H, m), 4.36 (2H, t), 5.10-5.17 (1H, m), 6, 97 (1H, d), 7.93 (1H, d), 8.12 (1H, d), 8.21 (1H, dd), 8.43 (1H, s), 8.68 (1H, d ), 8.89 (1H,s). Mass spectrum: m/z (ES+)[M+H]+ = 502.

[00562] Example 34: NMR spectrum: 1H NMR (300 MHz, DMSO-d6) δ 1.78-1.85 (4H, m), 2.05-2.18 (3H, m), 2.66 -2.80 (3H, m), 3.363.49 (8H, m), 3.94 (1H, d), 4.12-4.35 (2H, m), 4.38 (2H, t), 4.94-4.98 (1H, m), 7.00 (1H, d), 7.92 (1H, d), 8.13-8.20 (2H, m), 8.33 (1H, s), 8.63 (1H, s), 8.90 (1H, s). Mass spectrum: m/z (ES+)[M+H]+ = 474.3.

[00563] Example 35: NMR spectrum: 1H NMR (400 MHz, DMSO-d6) δ 1.64 - 1.75 (4H, m), 1.94 (2H, p), 2.45 (3H, d ), 2.53 - 2.58 (3H, m), 2.75 - 2.88 (2H, m), 2.94 - 3.08 (2H, m), 3.21 (3H, s), 3.87 (1H, p), 4.39 (2H, t), 5.08 (1H, p), 6.97 (1H, d), 7.90 (1H, dd), 8.09 (1H , d), 8.19 (1H, dd), 8.43 (1H, d), 8.65 (1H, s), 8.67 (1H, d), 11.50 (1H, s), m /z: ES+ [M+H]+ 474, Mass spectrum: m/z (ES+)[M+H]+ = 474.

[00564] Example 36: NMR spectrum: 1H NMR (300 MHz, DMSO-d6) δ 1.38 (2H, d), 1.46-1.53 (4H, m), 1.85-1.92 (4H, m), 2.27-2.42 (6H, m), 2.67-2.80 (2H, m), 3.52 (2H, t), 4.08 (2H, dd), 4.33 (2H, t), 5.10 (1H, p), 6.97 (1H, d), 7.93 (1H, d), 8.09 (1H, d), 8.12 (1H , d), 8.20 (1H, dd), 8.42 (1H, s), 8.65 (1H, s). Mass spectrum: m/z (ES+)[M+H]+ = 488.

[00565] Example 37: NMR spectrum: 1H NMR (400 MHz, DMSO-d6) δ 1.40 (2H, d), 1.50 (4H, q), 1.92 (4H, dq), 2, 3 - 2.45 (6H, m), 2.66 - 2.8 (2H, m), 3.52 (3H, s), 3.59 (2H, t), 4.07 (2H, dd) , 4.37 (2H, t), 5.09 - 5.2 (1H, m), 6.96 - 6.99 (1H, d), 7.96 (1H, dd), 8.15 (1H , d), 8.18 - 8.21 (1H, m), 8.44 (1H, s), 8.66 (1H, d), 8.90 (1H, s). Mass spectrum: m/z (ES+)[M+H]+ = 502.46.

[00566] Example 38: NMR spectrum: 1H NMR (400 MHz, DMSO-d6) δ 1.74 (2H, p), 1.96 (2H, p), 2.47 (2H, t), 2, 78 - 2.87 (2H, m), 3.01 (2H, qd), 3.10 (4H, t), 3.21 (3H, s), 3.51 (3H, s), 3.87 (1H, p), 4.35 (2H, t), 5.08 - 5.18 (1H, m), 6.93 - 6.97 (1H, d), 7.92 (1H, dd), 8.12 (1H, d), 8.18 - 8.21 (1H, d), 8.43 (1H, d), 8.65 - 8.68 (1H, m), 8.88 (1H, d). s). Mass spectrum: m/z (ES+)[M+H]+ = 474.43.

[00567] Example 39: NMR spectrum: 1H NMR (300 MHz, DMSO-d6) δ 1.74-1.78(2H, m), 1.81-1.93(2H, m), 2.00 -2.09(2H, m), 2.652.77(4H, m), 3.31-3.36(4H, m), 3.51(3H, s), 3.58(2H, t), 4.04-4.09(2H, m), 4.34(2H, t), 5.14(1H, p), 6.97(1H, d), 7.94(1H, dd), 8 .13 (1H, d), 8.20(1H, dd), 8.22(1H, s), 8.66 (1H, d), 8.90(1H, s). Mass spectrum: m/z (ES+)[M+H]+ = 474.

[00568] The fluorine intermediates required for Examples 27 - 39 have already been described or were prepared from the appropriate bromine intermediates as described below: Intermediate P: 8-(6-fluoropyridin-3-yl)-3-methyl- 1-[(3 S )-oxan-3-yl]imidazo[5,4-c]quinolin-2-one

[00569] Pd(Ph3P)4 (0.160 g, 0.14 mmol) was added to 8-bromo-3-methyl-1-[(3S)-oxan-3-yl]imidazo[5,4-c]quinoline -2-one (1 g, 2.76 mmol), (6-fluoropyridin-3-yl)boronic acid (0.506 g, 3.59 mmol) and Cs2CO3 (1.799 g, 5.52 mmol) in 1,4- dioxane (23 mL) and water (3 mL) under nitrogen. The resulting mixture was stirred at 100°C for 3 hours then allowed to cool and the solvent removed under reduced pressure. The crude product was purified by FCC, gradient elution from 0 to 7% MeOH in DCM, providing the desired material (0.905 g, 87%) as a yellow solid. NMR spectrum: 1H NMR (300 MHz, DMSO-d6) δ 1.83-1.86 (2H, m), 2.15-2.19 (1H, m), 2.49-2.64 (1H , m), 3.38-3.41 (1H, m), 3.49 (3H, s), 3.93 (1H, d), 4.15-4.26 (2H, m), 4.915, 10 (1H,m), 7.42 (1H, dd), 7.96 (1H,dd), 8.13 (1H, d), 8.38 (1H,s), 8.44 (1H, td ), 8.72 (1H,d), 8.96 (1H,s). Mass spectrum: m/z (ES+)[M+H]+ = 379.1.

[00570] The following fluorine intermediates were prepared analogously from (6-fluoropyridin-3-yl)boronic acid and the appropriate bromine intermediates, the synthesis of which has already been described: * The reaction was stirred at 80°C for 2 hours. 2 * The reaction was carried out using chloro(2-dicyclohexylphosphine-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)] palladium(II) as the catalyst and stirred at 90°C for 2 hours. 3 ** The reaction was carried out with a 1:2 mixture of sodium tetrachloropalladate and 3-(di-tert-butylphosphino)propane-1-sulfonic acid (0.05 M in water) as the catalyst and ligand and K2CO3 as the base. The reaction was stirred at 80°C for 3 hours.

[00571] Intermediate Q: NMR spectrum: 1H NMR (300 MHz, DMSO-d6) δ 1.80-1.83 (2H, m), 2.15-2.18 (1H, m), 2.49 -2.73 (1H, m), 3.37-3.41 (1H, m), 3.49 (3H, s), 3.93 (1H, d), 4.16-4.26 (2H , m), 4.905.10 (1H, m), 7.42 (1H, dd), 7.97 (1H, dd), 8.14 (1H, d), 8.38 (1H, s), 8 .45 (1H, td), 8.71 (1H,d), 8.95 (1H,s). Mass spectrum: m/z (ES+)[M+H]+ = 379.

[00572] Intermediate R: NMR spectrum: 1H NMR (300 MHz, DMSO-d6) δ 2.76 - 2.81 (2H, m), 2.91 - 3.05 (2H, m), 3.13 (3H, s), 3.49 (3H, s), 3.78-3.82 (1H, m), 5.07-5.10 (1H, m), 7.40 (1H, dd), 7.94 (1H, d), 8.32 (1H, td), 8.45 (d) 8.59 (1H, s), 8.95 (1H, s). Mass spectrum: m/z (ES+)[M+H]+ = 397.

[00573] Intermediate S: NMR spectrum: 1H NMR (400 MHz, DMSO-d6) δ 2.83 (2H, s), 3.01 (2H, d), 3.20 (3H, s), 3, 51 (3H, s), 3.86 (1H, s), 5.07 - 5.18 (1H, m), 7.37 (1H, d), 7.96 (1H, d), 8.16 (1H, d), 8.49 (2H, d), 8.75 (1H, s), 8.92 (1H, s). Mass spectrum: m/z (ES+)[M+H]+ = 379.

[00574] Intermediate T: NMR spectrum: 1H NMR (300 MHz, DMSO-d6) δ 1.90-1.96 (2H, m), 2.65-2.79 (2H, s), 3.65 (2H, t), 4.014.11 (2H, m), 5.06-5.14 (1H, m), 7.40 (1H, dd), 8.02 (1H, dd), 8.15 ( 1H, d), 8.44-8.50 (2H, m), 8.71 (1H, s), 8.75 (1H, dd), 11.75 (1H, bs). Mass spectrum: m/z (ES+)[M+H]+ = 365.

[00575] Intermediate U: NMR spectrum: 1H NMR (400 MHz, DMSO-d6) δ 2.71 - 2.84 (3H, m), 2.97 - 3.09 (2H, m), 3.20 (3H, s), 3.86 (1H, p), 5.09 (1H, ddd), 7.35 (1H, dd), 7.83 (1H, dd), 8.07 (1H, d) , 8.42 - 8.5 (2H, m), 8.63 (1H, s), 8.73 (1H, d). Mass spectrum: m/z (ES+)[M+H]+ = 365, 367. Example 40 3-Methyl-8-[6-(3-methylaminopropoxy)pyridin-3-yl]-1-(oxan-4) -yl)imidazo[5,4-c]quinolin-2-one

[00576] Sodium hydride (50.7 mg, 2.11 mmol) was added to tert-butyl (3-hydroxypropyl)(methyl)carbamate (200 mg, 1.06 mmol) in DMF (5 mL) at room temperature environment under the air flow. The resulting solution was stirred for 1 hour, then 8-(6-fluoropyridin-3-yl)-3-methyl-1-(oxan-4-yl)imidazo[5,4-c]quinolin- 2-one (200 mg, 0.53 mmol) was added and the resulting solution stirred at room temperature overnight. The reaction mixture was quenched with water (20ml), extracted with EtOAc (5x20ml) and the organic layers combined and washed with water (3x50ml). The organic layer was dried with Na2SO4, filtered and evaporated to give a white solid (262mg, 91%). This material was dissolved in DCM (10 mL) and TFA (5 mL, 64.90 mmol) added. The reaction was stirred at room temperature for 1 hour, then the solvent was removed in vacuo. The crude product was purified by preparative HPLC (XSelect CSH Prep C18 OBD column, 5 µm silica, 19 mm diameter, 150 mm length) using mixtures of decreasing polarity water (containing 0.1% NH4HCO3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to provide the desired material (60.0mg, 27.7%) as a white solid. NMR spectrum: 1H NMR (300 MHz, DMSO-d6) δ 1.86-1.94 (4H, m), 2.30 (3H, s), 3.08 (2H, t), 2.71 ( 2H, dd), 3.52 (3H, s), 3.58 (2H, t), 4.05 (2H, dd), 4.36 (2H, t), 5.15 (1H, p), 6.98 (1H, d), 7.94 (1H, dd), 8.12 (1H, d), 8.20 (1H, dd), 8.42 (1H, s), 8.65 (1H , d), 8.90 (1H, s). Mass spectrum: m/z (ES+)[M+H]+ = 448.

[00577] The following compounds were prepared analogously from tert-butyl (3-hydroxypropyl)(methyl)carbamate and the appropriate fluorine intermediate. * The initial deprotonation and displacement reaction was carried out in THF.

[00578] Example 41: NMR spectrum: 1H NMR (300 MHz, DMSO-d6) δ 1.79-1.84 (2H, m), 2.06-2.21 (3H, m), 2.67 (3H, s), 2.68-2.80 (1H, m), 3.10 (2H, t), 3.40-3.60 (5H, m), 3.94 (1H, d), 4.12-4.25 (2H, m), 4.43 (2H, t), 5.20 (1H, p), 7.08 (1H, d), 8.10 (1H, d), 8 .19-8.28 (1H, m), 8.40 (1H, s), 8.68 (1H, s), 9.06 (1H, s). Mass spectrum: m/z (ES+)[M+H]+ = 448.2.

[00579] Example 42: NMR spectrum: 1H NMR (300 MHz, DMSO-d6) δ 1.82-1.92 (2H, m), 2.29 (3H, s), 2.62 (2H, t ), 2.77-2.88 (2H, m), 3.00 (2H, q), 3.21 (3H, s), 3.50 (3H, s), 3.87 (1H, p) , 4.38 (2H, t), 5.10 (1H, p), 6.98 (1H, d), 7.91 (1H, d), 8.10 (1H, d), 8.21 ( 1H, dd), 8.42 (1H, s), 8.67 (1H, s), 8.89 (1H, s). Mass spectrum: m/z (ES+)[M+H]+ = 448.

[00580] Example 43: NMR spectrum: 1H NMR (300 MHz, DMSO-d6) δ 1.84 (2H, m), 2.10 (3H, m), 2.70 (4H, m), 3, 10 (2H, m), 3.40 (1H, m), 3.50 (3H, s), 3.92 (1H, d), 4.18 (2H, m), 4.43 (2H, t ), 5.02 (1H, bs), 7.03 (1H, d), 8.03 - 9.01 (6H, m). Mass spectrum: m/z (ES+)[M+H]+ = 448.2.

[00581] The preparation of the fluorine intermediates required for Examples 40 - 43 have already been described. Example 44 8-[6-[3-(Dimethylamino)propoxy]-3-pyridyl]-3-methyl-1-[(3 R )-tetrahydrofuran-3-yl]imidazo[4,5-c salt methanesulfonic acid ]quinolin-2-one

[00582] N,N-Dimethyl-3-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl]oxypropan-1-amine (106 mg, 0.34 mmol), 2M K2CO3 (0.718 mL, 1.44 mmol) and 8-bromo-3-methyl-1-[(3R)-tetrahydrofuran-3-yl]imidazo[4,5-c ]quinolin-2-one (100 mg, 0.29 mmol) were suspended in dioxane (3 mL) and then degassed with nitrogen. To this suspension, dichloro[1,1'-bis(di-tert-butylphosphino)ferrocene]palladium(II) (18.72 mg, 0.03 mmol) was added and the resulting suspension was heated in a sealed flask. microwave at 80°C for 1 hour. The reaction was partitioned between water and DCM and the organic layer concentrated under reduced pressure. The crude product was purified by FCC with gradient elution from 0 to 10% methanolic ammonia in DCM, providing the desired compound (90 mg). The desired material can be isolated as the methanesulfonic acid salt by dissolving the isolated material in DCM (10 mL) then adding 1M methanesulfonic acid in DCM (0.201 mL, 0.20 mmol) and stirring the mixture at room temperature for 1 hour. The solvent was removed in vacuo and the solid triturated in Et2O to give the methanesulfonic acid salt as a beige solid (64.0 mg). NMR spectrum (methanesulfonic acid salt): 1H NMR (500 MHz, DMSO-d6) δ 2.08 - 2.24 (2H, m), 2.31 (3H, s), 2.33 - 2.46 (1H, m), 2.54 (1H, s), 2.83 (6H, s), 3.18 - 3.29 (2H, m), 3.55 (3H, s), 3.91 ( 1H, td), 4.09 - 4.23 (2H, m), 4.27 (1H, td), 4.42 (2H, t), 5.79 - 5.9 (1H, m), 7 .00 (1H, dd), 7.98 (1H, dd), 8.16 (1H, d), 8.26 (1H, dd), 8.61 (1H, d), 8.71 (1H, dd), 8.94 (1H, s), 9.34 (1H, s). Mass spectrum: m/z (ES+)[M+H]+ = 448.

[00583] The following compounds were prepared analogously from the appropriate bromo intermediate.

[00584] Example 45: NMR spectrum (methanesulfonic acid salt): 1H NMR (500 MHz, DMSO-d6) δ 2.11 - 2.21 (2H, m), 2.29 - 2.33 ( 3H, m), 2.32 - 2.46 (1H, m), 2.52 - 2.6 (1H, m), 2.83 (6H, s), 3.21 - 3.28 (2H, m). m), 3.55 (3H, s), 3.91 (1H, td), 4.12 - 4.23 (2H, m), 4.27 (1H, td), 4.42 (2H, t ), 5.79 - 5.9 (1H, m), 7.00 (1H, dd), 7.98 (1H, dd), 8.16 (1H, d), 8.27 (1H, dd) , 8.61 (1H, d), 8.71 (1H, d), 8.94 (1H, s), 9.33 (1H, s). Mass spectrum: m/z (ES+)[M+H]+ = 448.

[00585] Example 46: NMR spectrum (free base): 1H NMR (500 MHz, DMSO-d6) δ 1.39 (3H, d), 1.92 - 2.01 (1H, m), 2.01 - 2.11 (1H, m), 2.34 (6H, s), 2.43 (1H, dd), 2.51 - 2.61 (2H, m), 2.73 (1H, dd), 3.24 (2H, pd), 3.58 (3H, s), 5.31 - 5.41 (1H, m), 5.43 - 5.53 (1H, m), 6.89 (1H, m). dd), 7.78 (1H, dd), 7.89 (1H, dd), 8.18 - 8.22 (1H, m), 8.32 (1H, d), 8.51 (1H, dd ), 8.69 (1H, s). NMR spectrum (methanesulfonic acid salt): 1H NMR (500 MHz, DMSO-d6) δ 1.76 - 2.01 (2H, m), 2.08 - 2.22 (2H, m), 2 .31 (3H, s), 2.41 - 2.49 (2H, m), 2.83 (6H, s), 3.09 (2H, pd), 3.18 - 3.28 (2H, m ), 3.51 (3H, s), 4.42 (2H, t), 5.51 (1H, p), 7.01 (1H, dd), 7.93 (1H, dd), 8.13 (1H, d), 8.24 (1H, dd), 8.42 (1H, d), 8.69 (1H, dd), 8.89 (1H, s), 9.34 (1H, s) . Mass spectrum: m/z (ES+)[M+H]+ = 432.

[00586] The bromine intermediates needed to prepare Examples 44-46 were prepared as described below:Intermediate V1: 8-Bromo-3-methyl-1-[(3 R )-tetrahydrofuran-3-yl]imidazo[ 4,5-c]quinolin-2-one

[00587] Tetrabutylammonium bromide (0.222 g, 0.69 mmol) was added to 8-bromo-1-[(3R)-tetrahydrofuran-3-yl]-3H-imidazo[4,5-c]quinolin- 2-one (2.3 g, 6.88 mmol), methyl iodide (1.291 mL, 20.65 mmol) and NaOH (0.551 g, 13.77 mmol) in DCM (65 mL) and water (39 mL) and the resulting mixture stirred at room temperature overnight. The solvent was removed under reduced pressure and the crude product purified by FCC with gradient elution from 2 to 5% MeOH in DCM, providing the desired material as a yellow solid (1.80 g, 75%). NMR spectrum: 1H NMR (400 MHz, CDCl3) δ 2.41-2.49 (1H, m), 2.59-2.65 (1H, m), 3.62 (3H, s), 4, 00-4.06 (1H, m), 4.21-4.48 (2H, m), 4.49-4.52 (1H, m), 5.69-5.77 (1H, m), 7.69 (1H, d), 8.02 (1H, d), 8.64 (1H, s), 8.74 (1H, s). Mass spectrum: m/z (ES+)[M+H]+ = 350.

[00588] The following compounds were prepared analogously from the appropriate intermediate:

[00589] Intermediate W1: NMR spectrum: 1H NMR (400 MHz, DMSO-d6) δ 2.40 - 2.48 (1H, m), 2.58 - 2.67 (1H, m), 3.63 (3H, s), 3.98 - 4.05 (1H, m), 4.19 - 4.28 (2H, m), 4.46 - 4.51 (1H, td), 5.68 - 5 .76 (1H, m), 7.72 (1H, d), 8.07 (1H, d), 8.67 (1H, d), 8.76 (1H, s). Mass spectrum: m/z (ES+)[M+H]+ = 348.

[00590] Intermediate X1: NMR spectrum: 1H NMR (400 MHz, CDCl3) δ 1.95 - 2.12 (2H, m), 2.52 - 2.59 (2H, m), 3.17 - 3 .28 (2H, m), 3.59 (3H, s), 5.18 - 5.27 (1H, m), 7.8 (1H, d), 8.02 (1H, d), 8, 37 (1H, d), 8.70 (1H, s). Mass spectrum: m/z (ES+)[M+H]+ = 332. Intermediate V2:8-Bromo-1-[(3 R )-tetrahydrofuran-3-yl]-3H-imidazo[4,5 -c]quinolin-2-one

[00591] Triethylamine (2.60 mL, 18.69 mmol) was added to 6-bromo-4-[[(3R)-tetrahydrofuran-3-yl]amino]quinoline-3-carboxylic acid (2.1 g, 6.23 mmol) in DMF (30 mL) and the resulting mixture stirred at room temperature for 1 hour. Diphenyl phosphorazidate (3.43 g, 12.46 mmol) was added and the resulting mixture was stirred at 60 °C overnight. The reaction mixture was diluted with water (300 mL) and the solids collected by filtration to provide the desired material as a yellow solid (2.0 g, 96%). NMR spectrum: 1H NMR (300 MHz, DMSO-d6) δ 2.42-2.45 (2H, m), 3.85-3.90 (1H, m), 4.05-4.16 (2H , m), 4.164.25 (1H, m), 5.62-5.72 (1H, m), 7.16-7.18 (1H, m), 7.74 (1H, d), 7. 97 (1H, d), 8.68 (1H, s), 8.73 (1H, s), 11.84 (1H, s). Mass spectrum: m/z (ES+)[M+H]+ = 334.

[00592] The following compounds were prepared analogously from the appropriate intermediate:

[00593] Intermediate W2: Mass spectrum: m/z (ES+)[M+H]+ = 334.

[00594] Intermediate X2: Mass spectrum: m/z (ES+)[M+H]+ = 318. Intermediate V3: 6-Bromo-4-[[(3 R )-tetrahydrofuran-3-yl] acid amino]quinoline-3-carboxylic acid

[00595] Sodium hydroxide (0.657 g, 16.43 mmol) was added to ethyl 6-bromo-4-[[(3R)-tetrahydrofuran-3-yl]amino]quinoline-3-carboxylate (3 g , 8.21 mmol) in THF (60 mL) and water (30 mL) and the resulting mixture stirred at 60 °C overnight. The aqueous component was removed under reduced pressure, and the remaining solution was adjusted to pH 6 with 2M HCl. The solids were collected by filtration and dried in an oven to provide the desired material as a white solid (2.1g, 76%). NMR spectrum: 1H NMR (300 MHz, MeOH-d4) δ 2.05-2.08 (1H, m), 2.38-2.48 (1H, m), 3.72-3.93 (4H , m), 4.83-5.01 (1H, m) 7.09 (1H, d), 8.04 (1H, d), 8.55 (1H, s), 8.95 (1H, s ). Mass spectrum: m/z (ES+)[M+H]+ = 339.

[00596] The following compounds were prepared analogously from the appropriate intermediate:

[00597] Intermediate W3: NMR spectrum: 1H NMR (400 MHz, DMSO-d6) δ 1.95 - 2.05 (1H, m), 2.31 - 2.41 (1H, m), 3.79 - 3.87 (2H, m), 3.89 - 3.95 (2H, m), 4.82 - 4.92 (1H, m), 7.78 (1H, d), 7.92 - 7 .94 (1H, m), 8.44 (1H, d), 8.90 (1H, s), 13.3 (1H, s). Mass spectrum: m/z (ES+)[M+H]+ = 337.

[00598] Intermediate X3: NMR spectrum: 1H NMR (400 MHz, DMSO-d6) δ 1.81 - 1.95 (3H, m), 2.01 - 2.15 (3H, m), 4.53 - 4.55 (1H, m), 7.74 (1H, d), 7.88 (1H, d), 8.25 (1H, s), 8.89 (1H, s), 13.27 ( 1H, s). Mass spectrum: m/z (ES+)[M+H]+ = 321.Intermediate V4:6-bromo-4-[[(3 R )-tetrahydrofuran-3-yl]amino]quinoline-3-carboxylate of ethyl

[00599] DIPEA (7.77 mL, 44.51 mmol) was added to ethyl 6-bromo-4-chloroquinoline-3-carboxylate (3.5 g, 11.13 mmol) and (R)-tetrahydrofuran -3-amine (1939 g, 22.25 mmol) in DMF (40 mL) and the resulting mixture stirred at 100 °C overnight. The reaction mixture was cooled, filtered and the solid dried in an oven to provide the desired material as a white solid (3.00g, 73.8%). NMR spectrum: 1H NMR (300 MHz, MeOH-d4) δ 1.35 (3H, t), 1.96-2.01 (1H, m), 2.33-2.38 (1H, m), 3.73 (2H, m), 3.94 (2H, m), 4.67 (1H, m), 7.77-7.89 (2H, m), 8.50 (1H, s), 8 .75 (1H, d), 8.87 (1H, s). Mass spectrum: m/z (ES+)[M+H]+ = 365.

[00600] The following compounds were prepared analogously from the appropriate intermediate. * The reaction was stirred at 60°C for 16 hours.

[00601] Intermediate W4: NMR spectrum: 1H NMR (400 MHz, CDCl3) δ 1.45 (3H, t), 2.12 - 2.19 (1H, m), 2.48 - 2.55 (1H , m), 3.87 - 4.04 (2H, m), 4.12 (2H, td), 4.43 (2H, q), 4.76 - 4.86 (1H, m), 7, 80 (1H, dd), 7.95 (1H, d), 8.34 (1H, d), 9.14 (1H, s), 9.64 (1H, s). Mass spectrum: m/z (ES+)[M+H]+ = 365.

[00602] Intermediate X4: NMR spectrum: 1H NMR (400 MHz, CDCl3) δ 1.45 (3H, t), 1.77 - 2.01 (2H, m), 2.16 - 2.31 (2H , m), 2.58 - 2.71 (2H, m), 4.45 (3H, m), 7.74 (1H, dd), 7.82 (1H, d), 8.23 (1H, d), 9.09 (1H, s), 9.57 (1H, d). Mass spectrum: m/z (ES+)[M+H]+ = 349.

[00603] The preparation of ethyl 6-bromo-4-chloroquinoline-3-carboxylate has been previously described.Example 47 Salt of 7-fluoro-3-methyl-8-[6-[3-(1-piperidyl) methanesulfonic acid propoxy]-3-pyridyl]-1-[(3 S )-tetrahydropyran-3-yl]imidazo[4,5-c]quinolin-2-one

[00604] 3-(Piperidin-1-yl)propan-1-ol (43.4 mg, 0.30 mmol) in THF (0.5 mL) was added dropwise to a stirred suspension of hydrogen hydride. sodium (24.22 mg, 0.61 mmol) in THF (0.5 mL) at room temperature. The resulting suspension was stirred for 10 minutes under nitrogen, then 7-fluoro-8-(6-fluoro-3-pyridyl)-3-methyl-1-[(3S)-tetrahydropyran-3- yl]imidazo[4,5-c]quinolin-2-one (100 mg, 0.25 mmol) in DMF (1.5 mL) and the reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with EtOAc (40ml), washed twice with water (20ml), the organic layer dried over MgSO 4 , filtered and evaporated to give the crude product. The crude product was purified by FCC, gradient elution from 0 to 4% 2N methanolic ammonia in DCM, providing the desired material as a white solid (80 mg, 61.0%). The isolated material (79 mg) was dissolved in DCM (2 mL) and methanesulfonic acid (16.07 mg, 0.17 mmol) in DCM was added. The solution was evaporated until completely dry to give the methanesulfonic acid salt of the desired material as a pale yellow solid (97 mg). NMR spectrum (methanesulfonic acid salt): 1H NMR (500 MHz, DMSO-d6) δ 1.40 (1H, dd), 1.55 - 1.92 (6H, m), 2.06 - 2.26 (3H, m), 2.31 (3H, s), 2.59 - 2.77 (1H, m), 2.82 - 3.03 (2H, m), 3.19 - 3.29 (2H, m) , m), 3.38 (2H, td), 3.49 (5H, s), 3.84 - 3.95 (1H, m), 4.12 (1H, dd), 4.19 (1H, t), 4.44 (2H, t), 4.76 - 5.07 (1H, m), 7.04 (1H, dd), 7.96 (1H, d), 8.11 (1H, dt ), 8.26 (1H, d), 8.54 (1H, s), 8.95 (1H, s), 9.01 (1H, s). Mass spectrum: m/z (ES+)[M+H]+ = 520.2.

[00605] 7-Fluoro-8-(6-fluoro-3-pyridyl)-3-methyl-1-[(3S)-tetrahydropyran-3-yl]imidazo[4,5-c]quinolin-2- one was prepared as described below: Intermediate K4: 7-Fluoro-8-(6-fluoro-3-pyridyl)-3-methyl-1-[(3 S )-tetrahydropyran-3-yl]imidazo[4, 5-c]quinolin-2-one

[00606] 8-Bromo-7-fluoro-3-methyl-1-[(3S)-oxan-3-yl]imidazo[5,4-c]quinolin-2-one (250 mg, 0.66 mmol) , (6-fluoropyridin-3-yl)boronic acid (120 mg, 0.85 mmol) and 2M K2CO3 (1 mL, 2.00 mmol) were suspended in 1,4-dioxane (3 mL), degassed, then [ Pd-118] (22 mg, 0.03 mmol) was added. The reaction was heated to 80°C for 1 hour under nitrogen then allowed to cool. The reaction mixture was diluted with EtOAc (50 mL), then washed with water (2 x 25 mL), brine, the organic phase dried over MgSO 4 , filtered and concentrated in vacuo. The crude product was purified by FCC, gradient elution from 0 to 4% 2N methanolic ammonia in DCM, providing the desired material as an off-white solid (205 mg, 79%). NMR spectrum: 1H NMR (500 MHz, DMSO-d6) δ 1.71 - 1.87 (2H, m), 2.14 (1H, d), 2.57 - 2.76 (1H, m), 3.32 - 3.42 (1H, m), 3.49 (3H, s), 3.90 (1H, d), 4.06 - 4.16 (1H, m), 4.21 (1H, t), 4.79 - 5.1 (1H, m), 7.36 - 7.54 (1H, m), 7.97 (1H, d), 8.32 (1H, d), 8.37 (1H, tt), 8.62 (1H, s), 8.95 (1H, s). Mass spectrum: m/z (ES+)[M+H]+ = 397.

[00607] The preparation of 8-bromo-7-fluoro-3-methyl-1-[(3S)-oxan-3-yl]imidazo[5,4-c]quinolin-2-one has been previously described.Example 48 8-[6-[3-(Dimethylamino)propoxy]-2-fluoro-3-pyridyl]-7-fluoro-3-methyl-1-[(3S)-tetrahydropyran-3-yl]imidazo[ salt methanesulfonic acid 4,5-c]quinolin-2-one

[00608] Chloro(2-dicyclohexylphosphine-2',4',6'-triisopropyl-1,1-biphenyl)[2-(2-amino-1,1-biphenyl)]palladium (II) (103 mg , 0.13 mmol) was added to 3-[6-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl]oxy-N ,N-dimethylpropan-1-amine (468 mg, 1.44 mmol), 8-bromo-7-fluoro-3-methyl-1-[(3S)-oxan-3-yl]imidazo[5,4-c ]quinolin-2-one (500 mg, 1.32 mmol) and cesium carbonate (1285 mg, 3.95 mmol) in 1,4-dioxane (5 mL) and water (2.5 mL). The resulting mixture was stirred at 80 °C for three hours, then allowed to cool. The reaction mixture was diluted with EtOAc (100ml), washed twice with water (50ml), the organic layer dried over MgSO 4 , filtered and evaporated to give the crude product. The crude product was purified by FCC, gradient elution from 0 to 4% 2N methanolic ammonia in DCM, providing the desired material as a white solid (130 mg, 19.87%). The material can also be isolated as the methanesulfonic acid salt by dissolving in DCM and treating with 1 - 1.1 equivalents of methanesulfonic acid, then concentrating the mixture in vacuo and triturating the residue with Et2O. NMR spectrum (free base): 1H NMR (500 MHz, DMSO-d6) δ 1.77 (2H, t), 1.89 (2H, p), 2.11 (1H, d), 2.16 ( 6H, s), 2.37 (2H, t), 2.54 - 2.72 (1H, m), 3.33 - 3.42 (1H, m), 3.49 (3H, s), 3 .89 (1H, d), 4.08 (1H, dd), 4.23 (1H, t), 4.33 (2H, t), 4.85 (1H, s), 6.98 (1H, t). dd), 7.93 (1H, d), 8.11 - 8.24 (1H, m), 8.30 (1H, d), 8.93 (1H, s). NMR spectrum (methanesulfonic acid salt): 1H NMR (500 MHz, DMSO-d6) δ 1.66 - 1.89 (2H, m), 2.04 - 2.26 (3H, m), 2.31 (3H, s), 2.59 - 2.7 (1H, m), 2.84 (6H, d), 3.22 - 3.43 (3H, m), 3.50 (3H, s), 3.88 (1H, d), 4.03 - 4.15 (1H, m), 4.22 (1H, t), 4.39 (2H, t), 4.85 (1H, t), 7 .01 (1H, d), 7.96 (1H, d), 8.17 - 8.26 (1H, m), 8.30 (1H, d), 8.96 (1H, s), 9, 35 (1H, s). Mass spectrum: m/z (ES+)[M+H]+ = 498.

[00609] The following compounds were prepared analogously from the appropriate intermediates.

[00610] Example 49: NMR spectrum (free base): 1H NMR (500 MHz, DMSO-d6) δ 1.82 - 1.95 (2H, m), 2.16 (6H, s), 2.36 (3H, t), 2.52 - 2.59 (1H, m), 3.54 (3H, s), 3.87 (1H, d), 4.11 (2H, dd), 4.21 ( 1H, d), 4.31 (2H, t), 5.76 (1H, s), 6.94 (1H, dd), 7.81 (1H, dt), 8.13 (1H, d), 8.20 (1H, dd), 8.57 (1H, d), 8.94 (1H, s). NMR spectrum (methanesulfonic acid salt): 1H NMR (500 MHz, DMSO-d6) δ 2.08 - 2.25 (2H, m), 2.31 (3H, s), 2.32 - 2.42 (1H, m), 2.52 - 2.59 (1H, m), 2.84 (6H, s), 3.2 - 3.28 (2H, m), 3.54 (3H, s), 3.8 - 3.97 (1H, m), 4.03 - 4.17 (2H, m), 4.22 (1H, td), 4.38 (2H, t), 5.64 - 5, 97 (1H, m), 6.97 (1H, d), 7.82 (1H, d), 8.15 (1H, d), 8.25 (1H, dd), 8.59 (1H, s ), 8.96 (1H, s), 9.35 (1H, s). Mass spectrum: m/z (ES+)[M+H]+ = 466.

[00611] Example 50: NMR spectrum (free base): 1H NMR (500 MHz, DMSO-d6) δ 1.89 (2H, p), 2.16 (6H, s), 2.36 (3H, t ), 2.52 - 2.6 (1H, m), 3.54 (3H, s), 3.79 - 3.98 (1H, m), 4.04 - 4.18 (2H, m), 4.21 (1H, td), 4.31 (2H, t), 5.76 (1H, d), 6.94 (1H, dd), 7.81 (1H, dt), 8.13 (1H , d), 8.20 (1H, dd), 8.57 (1H, d), 8.94 (1H, s). NMR spectrum (methanesulfonic acid salt): 1H NMR (500 MHz, DMSO-d6) δ 2.1 - 2.25 (2H, m), 2.33 (3H, s), 2.35 - 2.44 (1H, m), 2.53 - 2.61 (1H, m), 2.85 (6H, d), 3.26 (2H, s), 3.57 (3H, s), 3.81 - 3.98 (1H, m), 4.07 - 4.17 (2H, m), 4.19 - 4.29 (1H, m), 4.39 (2H, t), 5.71 - 5, 9 (1H, m), 6.99 (1H, d), 7.91 (1H, d), 8.20 (1H, d), 8.27 (1H, dd), 8.65 (1H, s ), 9.06 (1H, s), 9.40 (1H, s). Mass spectrum: m/z (ES+)[M+H]+ = 466.

[00612] Example 51: NMR spectrum (free base): 1H NMR (500 MHz, DMSO-d6) δ 1.79 - 1.95 (4H, m), 2.16 (6H, s), 2.37 (2H, t), 2.4 - 2.49 (2H, m), 3.07 (2H, td), 3.50 (3H, s), 4.32 (2H, t), 5.40 ( 1H, p), 6.95 (1H, d), 7.80 (1H, d), 8.11 (1H, d), 8.22 (1H, dd), 8.44 (1H, s), 8.90 (1H, s). NMR spectrum (methanesulfonic acid salt): 1H NMR (500 MHz, DMSO-d6) δ 1.78 - 1.99 (2H, m), 2.08 - 2.23 (2H, m), 2.31 (3H, s), 2.38 - 2.48 (2H, m), 2.84 (6H, s), 3.01 - 3.14 (2H, m), 3.2 - 3.29 (2H , m), 3.51 (3H, s), 4.38 (2H, t), 5.28 - 5.58 (1H, m), 6.98 (1H, d), 7.83 (1H, d), 8.15 (1H, d), 8.23 - 8.39 (1H, m), 8.46 (1H, s), 8.94 (1H, s), 9.38 (1H, s) ). Mass spectrum: m/z (ES+)[M+H]+ = 450.

[00613] Example 52: NMR spectrum (free base): 1H NMR (500 MHz, DMSO-d6) δ 1.83 - 1.96 (2H, m), 2.16 (6H, s), 2.36 (2H, t), 3.53 (3H, s), 4.32 (2H, t), 5.01 (2H, dd), 5.25 (2H, t), 5.95 - 6.24 ( 1H, m), 6.94 (1H, dd), 7.82 (1H, dt), 8.13 (1H, d), 8.19 (1H, dd), 8.39 (1H, s), 8.95 (1H, s). NMR spectrum (methanesulfonic acid salt): 1H NMR (500 MHz, DMSO-d6) δ 2.09 - 2.25 (2H, m), 2.32 (3H, s), 2.85 (6H, s) ), 3.22 - 3.29 (2H, m), 3.55 (3H, s), 4.39 (2H, t), 4.95 - 5.14 (2H, m), 5.26 ( 2H, t), 6.10 (1H, p), 6.98 (1H, d), 7.85 (1H, d), 8.17 (1H, d), 8.25 (1H, dd), 8.45 (1H, s), 9.01 (1H, s), 9.36 (1H, s) Mass spectrum: m/z (ES+)[M+H]+ = 452.

[00614] A 3-[6-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl]oxy-N,N-dimethylpropan- 1-amine used for these examples was prepared directly prior to use by treating 3-(5-bromo-6-fluoropyridin-2-yl)oxy-N,N-dimethylpropan-1-amine (1 equivalent) with 4,4,4 ',4'-5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (2 equivalents), potassium acetate (3 equivalents) and the complex [1, 1-bis(diphenylphosphino)ferrocene]dichloropalladium(II) with DCM (1:1) (0.1 equivalent) in 1,4-dioxane at 100 °C for 6 hours. This mixture was allowed to cool then used directly in the subsequent reaction.

[00615] The preparation of 3-(5-bromo-6-fluoropyridin-2-yl)oxy-N,N-dimethylpropan-1-amine and the necessary bromine intermediates has been previously described. Example 53 7-Fluoro-3-methyl-8-[6-[3-(1-piperidyl)propoxy]-3-pyridyl]-1-tetrahydropyran-4-yl-imidazo[4,5-c]quinoline -2-one

[00616] 3-(Piperidin-1-yl)propan-1-ol (0.053 mL, 0.35 mmol) was slowly added to a slurry of sodium hydride (31.5 mg, 0.79 mmol) in THF ( 7 mL) and the solution stirred at room temperature for 30 minutes. 7-Fluoro-8-(6-fluoro-3-pyridyl)-3-methyl-1-tetrahydropyran-4-yl-imidazo[4,5-c]quinolin-2-one (125 mg, 0.32 mmol) in THF (3 mL) to the reaction mixture via syringe over a period of 1 minute and the reaction stirred for 24 hours. The reaction was quenched with water, then extracted in DCM, the organic phase being separated and concentrated in vacuo. The crude product was purified by FCC, gradient elution from 1M methanolic ammonia 0 to 10% in DCM, and the resulting oil triturated with Et2O to provide the desired material as a white solid (92 mg, 56%). NMR spectrum: 1H NMR (500 MHz, CDCl3) δ 1.38 - 1.52 (2H, m), 1.61 (4H, p), 1.92 (2H, dd), 2.03 (2H, dt), 2.43 (4H, s), 2.47 - 2.58 (2H, m), 2.94 (2H, d), 3.53 - 3.63 (5H, m), 4.22 (2H, dd), 4.42 (2H, t), 5.01 (1H, s), 6.89 (1H, dd), 7.85 - 7.96 (2H, m), 8.26 ( 1H, s), 8.44 (1H, s), 8.71 (1H, s). Mass spectrum: m/z (ES+)[M+H]+ = 520.

[00617] The following compounds were prepared analogously from the appropriate intermediates. 1 The reaction was stirred at room temperature for 4 hours, then at 45°C for 2 hours. The material could also be isolated as the methanesulfonic acid salt by dissolving in DCM, treating with methanesulfonic acid (~1 equivalent) and concentrating in vacuo, then triturating the residue with Et2O. 2 * The reaction was stirred at room temperature for 4 hours, then at 45°C for 2 hours. 3 ** The reaction was stirred at room temperature for 4 hours, then at 45 °C for 2 hours. The material could also be isolated as the trifluoroacetic acid salt by dissolving in DCM, treating with trifluoroacetic acid (~1 equivalent) and concentrating in vacuo, then triturating the residue with Et2O. 4 *** The reaction was stirred at 50 °C overnight. The material could also be isolated as the methanesulfonic acid salt by dissolving in DCM, treating with methanesulfonic acid (~1 equivalent) and concentrating in vacuo. 5 **** The reaction was stirred at room temperature for 3 days. 6 ***** The reaction was stirred at room temperature for 2 hours.

[00618] Example 54: NMR spectrum (methanesulfonic acid salt): 1H NMR (500 MHz, CDCl3) δ 1.5 - 1.63 (2H, m), 1.7 - 1.98 (7H, m), 2.2 - 2.3 (2H, m), 2.45 (2H, dtd), 2.59 - 2.72 (2H, m), 2.82 (3H, s), 3.63 (3H, s), 3.79 - 3.87 (1H, m), 3.97 (1H, td), 4.19 - 4.33 (2H, m), 4.37 - 4.45 (1H , m), 4.46 (2H, t), 5.81 - 5.93 (1H, m), 6.87 (1H, dd), 7.84 (1H, dd), 8.05 (1H, dd). dd), 8.23 (1H, d), 8.56 (1H, dd), 8.58 (1H, d), 8.74 (1H, s). Mass spectrum: m/z (ES+)[M+H]+ = 488.

[00619] Example 55: NMR spectrum: 1H NMR (500 MHz, CDCh) δ 1.36 - 1.51 (2H, m), 1.61 (4H, p), 2.02 (2H, dt), 2.44 (5H, dtd), 2.48 - 2.55 (2H, m), 2.59 - 2.71 (1H, m), 3.63 (3H, s), 3.98 (1H, td), 4.21 - 4.33 (2H, m), 4.41 (3H, t), 5.86 (1H, qd), 6.87 (1H, dd), 7.85 (1H, dd ), 8.03 (1H, dd), 8.17 - 8.25 (1H, m), 8.5 - 8.59 (2H, m), 8.73 (1H, s). Mass spectrum: m/z (ES+)[M+H]+ = 488.

[00620] Example 56: NMR spectrum (free base): 1H NMR (500 MHz, CDCl3) δ 0.07 (1H, s), 1.45 (2H, s), 1.57 - 1.64 (3H , m), 1.99 - 2.06 (2H, m), 2.42 (4H, s), 2.47 - 2.54 (2H, m), 3.62 (3H, s), 4, 41 (2H, t), 5.18 - 5.25 (2H, m), 5.37 (2H, t), 6.08 - 6.18 (1H, m), 6.87 (1H, dd) , 7.87 (1H, dd), 7.97 (1H, dd), 8.24 (1H, d), 8.52 - 8.58 (2H, m), 8.75 (1H, s). NMR spectrum (trifluoroacetic acid salt): 1H NMR (500 MHz, DMSO-d6) δ 1.6 - 1.78 (4H, m), 1.85 (2H, d), 2.14 - 2.23 (2H, m), 2.94 (1H, s), 3.2 - 3.28 (2H, m), 3.51 (2H, d), 3.58 (3H, s), 4.44 ( 2H, t), 5.05 - 5.12 (2H, m), 5.28 (2H, t), 6.23 - 6.31 (1H, m), 7.02 (1H, d), 8 .05 - 8.37 (4H, m), 8.60 (1H, s), 8.74 (1H, d), 9.17 (1H, s), Mass spectrum: m/z (ES+)[ M+H]+ = 474.

[00621] Example 57: NMR spectrum (free base): 1H NMR (500 MHz, CDCl3) δ 1.45 (2H, d), 1.60 (4H, p), 1.86 - 2.12 (4H , m), 2.43 (4H, s), 2.47 - 2.63 (4H, m), 3.24 (2H, pd), 3.58 (3H, s), 4.42 (2H, t), 5.36 (1H, p), 6.89 (1H, dd), 7.77 (1H, dd), 7.90 (1H, dd), 8.21 (1H, d), 8, 32 (1H, d), 8.51 (1H, dd), 8.69 (1H, s). NMR spectrum (trifluoroacetic acid salt): 1H NMR (500 MHz, DMSO-d6) δ 1.42 (2H, s), 1.58 - 1.76 (4H, m), 1.82 - 1 .97 (4H, m), 2.14 - 2.28 (2H, m), 2.93 (2H, d), 3.06 - 3.14 (2H, m), 3.21 - 3.29 (2H, m), 3.53 (3H, s), 4.44 (2H, t), 5.51 - 5.58 (1H, m), 6.99 - 7.05 (1H, m), 8.00 (1H, d), 8.17 (1H, d), 8.26 (1H, d), 8.27 (1H, d), 8.46 (1H, s), 8.71 (1H , d), 8.97 (2H, s), Mass spectrum: m/z (ES+)[M+H]+ = 472.

[00622] Example 58: NMR spectrum (free base): 1H NMR (500 MHz, DMSO-d6) δ 1.67 - 1.73 (4H, m), 1.86 - 1.99 (4H, m) , 2.45 - 2.5 (6H, m), 2.57 (2H, t), 3.09 (2H, pd), 3.51 (3H, s), 4.39 (2H, t), 5.52 (1H, p), 6.99 (1H, dd), 7.92 (1H, dd), 8.12 (1H, d), 8.20 (1H, dd), 8.41 (1H , d), 8.67 (1H, dd), 8.88 (1H, s). NMR spectrum (methanesulfonic acid salt): 1H NMR (500 MHz, DMSO-d6) δ 1.84 - 1.98 (4H, m), 2.01 - 2.1 (2H, m), 2 .13 - 2.23 (2H, m), 2.32 (3H, s), 3.03 - 3.14 (4H, m), 3.28 - 3.36 (4H, m), 3.54 (3H, s), 3.58 - 3.67 (2H, m), 4.45 (2H, t), 5.52 - 5.63 (1H, m), 7.04 (1H, dd), 8.06 (1H, d), 8.19 (1H, d), 8.27 (1H, dd), 8.49 (1H, s), 8.71 - 8.74 (1H, m), 9 .03 (1H, s), 9.50 (1H, s). Mass spectrum: m/z (ES+)[M+H]+ = 458.

[00623] Example 59: NMR spectrum: 1H NMR (300 MHz, DMSO-d6) δ 1.68 - 1.86 (6H, m), 1.95 (2H, m), 2.15 (1H, m ), 2.51 - 2.75 (7H, m), 3.40 (1H, m), 3.49 (3H, s), 3.92 (1H, m), 4.15 (2H, m) , 4.38 (2H, m), 4.97 (1H, m), 6.98 (1H, m), 7.91 - 8.89 (6.82H, m). Mass spectrum: m/z (ES+)[M+H]+ = 488.3.

[00624] Example 60: NMR spectrum: 1H NMR (300 MHz, DMSO-d6) δ 1.80 (4H, m), 2.10 (3H, m), 2.68 (3H, m), 3, 35 (5H, m), 3.49 (3H, m), 3.92 (1H, m), 4.15 (2H, m), 4.33 (2H, m), 4.93 (1H, m ), 6.98 (1H, m), 7.91 - 8.89 (6.92H, m). Mass spectrum: m/z (ES+)[M+H]+ = 474.2.

[00625] The fluorine intermediates required for Examples 53 - 60 were previously described or were prepared from the appropriate bromo intermediates as described below:Intermediate F5: 7-Fluoro-8-(6-fluoro-3-pyridyl)- 3-methyl-1-tetrahydropyran-4-yl-imidazo[4,5-c]quinolin-2-one

[00626] (6-Fluoropyridin-3-yl)boronic acid (0.445 g, 3.16 mmol), 8-bromo-7-fluoro-3-methyl-1-(oxan-4-yl)imidazo[5.4 -c]quinolin-2-one (1 g, 2.63 mmol) and 2M K 2 CO 3 (3.95 mL, 7.89 mmol) were suspended in dioxane (3 mL) and water (0.75 mL). The reaction was degassed with nitrogen, then dichloro[1,1'-bis(di-tert-butylphosphino)ferrocene]palladium(II) (0.086 g, 0.13 mmol) was added and the reaction was heated to 80°C. °C for 1 hour in the microwave reactor. The mixture was allowed to cool, diluted with water and then extracted with DCM (2 x 100 mL). The combined organic phases were separated and concentrated in vacuo. The crude product was purified by FCC, gradient elution from 0 to 10% methanolic ammonia in DCM, providing the desired material as a beige solid (0.92 g, 88%). NMR spectrum: 1H NMR (500 MHz, DMSO-d6) δ 1.90 (2H, dd), 2.69 (2H, qt), 3.49 - 3.59 (5H, m), 3.97 - 4.06 (2H, m), 5.08 (1H, tt), 7.38 - 7.45 (1H, m), 7.96 (1H, d), 8.34 - 8.42 (2H, d). m), 8.61 - 8.65 (1H, m), 8.95 (1H, s). Mass spectrum: m/z (ES+)[M+H]+ = 397.

[00627] The following fluorine intermediates were prepared analogously:

[00628] Intermediate V5: NMR spectrum: 1H NMR (500 MHz, DMSO-d6) δ 2.34 - 2.45 (1H, m), 2.52 - 2.67 (1H, m), 3 .55 (3H, s), 3.91 (1H, td), 4.13 - 4.23 (2H, m), 4.27 (1H, td), 5.76 - 5.92 (1H, m ), 7.38 (1H, dd), 8.02 (1H, dd), 8.18 (1H, d), 8.49 (1H, ddd), 8.68 (1H, d), 8.77 (1H, d), 8.96 (1H, s). Mass spectrum: m/z (ES+)[M+H]+ = 365.

[00629] Intermediate W5: NMR spectrum: 1H NMR (500 MHz, DMSO-d6) δ 2.33 - 2.44 (1H, m), 2.53 - 2.67 (1H, m), 3.55 (3H, s), 3.91 (1H, td), 4.13 - 4.22 (2H, m), 4.27 (1H, td), 5.79 - 5.9 (1H, m), 7.3 - 7.41 (1H, m), 8.02 (1H, dd), 8.18 (1H, d), 8.49 (1H, ddd), 8.68 (1H, d), 8 .77 (1H, d), 8.96 (1H, s). Mass spectrum: m/z (ES+)[M+H]+ = 365.

[00630] Intermediate G5: NMR spectrum: 1H NMR (500 MHz, DMSO-d6) δ 3.55 (3H, s), 5.07 (2H, dd), 5.28 (2H, t), 6, 09 - 6.31 (1H, m), 7.29 - 7.43 (1H, m), 8.02 (1H, dd), 8.18 (1H, d), 8.49 (1H, ddd) , 8.56 (1H, d), 8.77 (1H, d), 8.97 (1H, s). Mass spectrum: m/z (ES+)[M+H]+ = 351.

[00631] Intermediate X5: NMR spectrum: 1H NMR (300 MHz, DMSO-d6) δ 1.77 - 2.01 (2H, m), 2.46 (2H, ddt), 3.09 (2H, pd ), 3.51 (3H, s), 5.53 (1H, p), 7.32 - 7.44 (1H, m), 7.96 (1H, dd), 8.15 (1H, d) , 8.43 - 8.54 (2H, m), 8.75 (1H, d), 8.91 (1H, s). Mass spectrum: m/z (ES+)[M+H]+ = 349,

[00632] The preparation of the bromine intermediates required for the above reactions has been previously described. Example 61 8-[2-Fluoro-6-(3-pyrrolidin-1-ylpropoxy)-3-pyridyl]-3-methyl-1-[(3 S )-tetrahydropyran-3-yl]imidazo[4, 5-c]quinolin-2-one

[00633] A solution of 3-(pyrrolidin-1-yl)propan-1-ol (0.047 g, 0.36 mmol) in THF (2 mL) was slowly added to a stirred suspension of sodium hydride (0.038 g, 0.96 mmol) in THF (2.0 mL) and the resulting suspension stirred at room temperature for 30 minutes. A solution of 8-(2,6-difluoro-3-pyridyl)-3-methyl-1-[(3S)-tetrahydropyran-3-yl]imidazo[4,5-c]quinolin-2 -one (0.12 g, 0.34 mmol) in DMF (2 mL) slowly and the reaction was stirred overnight. Water was added and the mixture was stirred for 30 minutes before being extracted with EtOAc (50 mL). The organic phases were washed with saturated brine (25ml), dried and evaporated to give the crude product. The crude product was purified by FCC, gradient elution from 0 to 10% (1% NH 3 in MeOH) in DCM, providing the desired material as a white solid (0.005 g, 4%). NMR spectrum: 1H NMR (500 MHz, CDCl3) δ 0.8 - 0.92 (1H, m), 1.21 - 1.29 (1H, m), 1.88 - 1.97 (2H, m ), 1.99 - 2.1 (4H, m), 2.23 (1H, d), 2.26 - 2.36 (2H, m), 2.77 (1H, qd), 2.9 - 3.16 (4H, m), 3.53 - 3.56 (1H, m), 3.57 (3H, s), 3.98 - 4.09 (1H, m), 4.12 - 4, 21 (1H, m), 4.45 (2H, t), 4.53 (1H, t), 4.9 - 5.01 (1H, m), 6.80 (1H, dd), 7.75 (1H, d), 7.93 (1H, dd), 8.22 (1H, d), 8.42 (1H, s), 8.71 (1H, s). Mass spectrum: m/z (ES+)[M+H]+ = 506.

[00634] The preparation of 8-(2,6-difluoro-3-pyridyl)-3-methyl-1-[(3S)-tetrahydropyran-3-yl]imidazo[4,5-c]quinolin-2 -one is described below: Intermediate D5: 8-(2,6-difluoro-3-pyridyl)-3-methyl-1-[(3 S )-tetrahydropyran-3-yl]imidazo[4,5-c ]quinolin-2-one

[00635] (2,6-Difluoropyridin-3-yl)boronic acid (158 mg, 0.99 mmol) and 8-bromo-3-methyl-1-[(3S)-oxan-3-yl]imidazo[5 ,4-c]quinolin-2-one (300 mg, 0.83 mmol) were suspended in dioxane (8 mL) and 2M K 2 CO 3 (2.071 mL, 4.14 mmol). The mixture was degassed with nitrogen and dichloro[1,1'-bis(di-tert-butylphosphino)ferrocene]palladium(II) (27.0 mg, 0.04 mmol) was added. The resulting suspension was heated at 80°C for 1 hour in a microwave reactor. The reaction mixture was diluted with EtOAc then washed with water (20 mL), brine, the organic phase dried over MgSO 4 , filtered and concentrated in vacuo. The crude product was purified by FCC, gradient elution from 0 to 10% MeOH in DCM, providing the desired material as a brown solid (196 mg, 60%). NMR spectrum: 1H NMR (500 MHz, DMSO-d6) δ 1.82 (2H, hept), 2.15 (1H, d), 2.55 - 2.67 (1H, m), 3.36 - 3.44 (1H, m), 3.51 (3H, s), 3.92 (1H, d), 4.06 - 4.14 (1H, m), 4.29 (1H, t), 4 .91 (1H, ddd), 7.42 (1H, dd), 7.85 - 7.91 (1H, m), 8.19 (1H, d), 8.47 (1H, s), 8. 56 (1H, dt), 8.95 (1H, s). Mass spectrum: m/z (ES+)[M+H]+ = 397.

[00636] The preparation of 8-bromo-3-methyl-1-[(3S)-oxan-3-yl]imidazo[5,4-c]quinolin-2-one has been previously described. Examples 62 and 63 8-[6-[3-(Dimethylamino)propoxy]-3-pyridyl]-7-fluoro-1-[(1 R ,3 R )-3-methoxycyclopentyl]-3-methyl-imidazo[4 ,5-c]quinolin-2-one and 8-[6-[3-(Dimethylamino)propoxy]-3-pyridyl]-7-fluoro-1-[(1 S ,3 S )-3-methoxycyclopentyl]- 3-methyl-imidazo[4,5-c]quinolin-2-one

[00637] 8-bromo-7-fluoro-1-[(1R,3R)-3-methoxycyclopentyl]-3-methyl-imidazo[4,5-c]quinolin-2-one:8-bromo-7-fluoro -1-[(1S,3S)-3-methoxycyclopentyl]-3-methyl-imidazo[4,5-c]quinolin-2-one (1:1 mixture) (400 mg, 1.01 mmol), N, N-dimethyl-3-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl]oxypropan-1-amine (227 mg, 1.01 mmol) and chloro(2-dicyclohexylphosphine-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (160 mg, 0.20 mmol) was suspended in a mixture of dioxane (5 mL) and water (0.5 mL) and Cs2CO3 (661 mg, 2.03 mmol) was added. The reaction was heated to 120°C for 1 hour in the microwave reactor, then allowed to cool. The reaction mixture was evaporated to dryness, redissolved in EtOAc (100 mL), washed sequentially with water (2 x 20 mL), and the organic layer dried with Na 2 SO 4 , filtered and evaporated to give the crude product. The crude product was purified by preparative HPLC, using mixtures of water of decreasing polarity (containing 0.03% NH 3 ) and MeCN as eluents, to provide the desired material in a racemic mixture. The mixture was purified by preparative chiral HPLC on a Chiralpak IA column, isocratically eluting with 10% isopropyl alcohol in heptane (modified with 0.2% diethylamine) as eluent to provide the two separate isomers.

[00638] Example 62: Isomer 1 (12 mg) NMR spectrum: 1H NMR (400 MHz, DMSO-d6) δ 1.73 - 1.85 (1 H, m), 1.84 - 1.96 (2 H, m), 2.09 - 2.26 (9 H, s), 2.35 - 2.50 (4 H, m), 3.21 - 3.26 (3 H, s), 3.45 - 3.58 (3H, s), 4.05 - 4.14 (1H, m), 4.33 - 4.42 (2H, m), 5.45 - 5.56 (1H, m). m), 6.97 - 7.04 (1H, m), 7.90 - 7.98 (1H, m), 8.01 - 8.09 (1H, m), 8.26 - 8 .33 (1H, m), 8.48 - 8.54 (1H, m), 8.91 - 8.96 (1H, s). Mass spectrum: m/z (ES+)[M+H]+ = 494.

[00639] Example 63: Isomer 2 (12 mg) NMR spectrum: 1H NMR (400 MHz, DMSO-d6) δ 1.75 - 1.82 (1H, m), 1.85 - 1.97 (2 H, m), 2.11 - 2.26 (9 H, s), 2.37 - 2.50 (4 H, m), 3.21 - 3.26 (3 H, s), 3.46 - 3.56 (3H, s), 4.07 - 4.13 (1H, m), 4.33 - 4.42 (2H, m), 5.47 - 5.58 (1H, m). m), 6.97 - 7.04 (1H, m), 7.90 - 7.98 (1H, m), 8.01 - 8.09 (1H, m), 8.27 - 8 .34 (1H, m), 8.49 - 8.54 (1H, s), 8.91 - 8.96 (1H, s). Mass spectrum: m/z (ES+)[M+H]+ = 494.

[00640] The preparation of 8-bromo-7-fluoro-1-[(1R,3R)-3-methoxycyclopentyl]-3-methyl-imidazo[4,5-c]quinolin-2-one:8-bromo- 7-Fluoro-1-[(1S,3S)-3-methoxycyclopentyl]-3-methyl-imidazo[4,5-c]quinolin-2-one (1:1 mixture) is described below: Intermediate Y1: 8- bromo-7-fluoro-1-[(1R,3R)-3-methoxycyclopentyl]-3-methyl-imidazo[4,5-c]quinolin-2-one and 8-bromo-7-fluoro-1-[ (1 S ,3 S )-3-methoxycyclopentyl]-3-methyl-imidazo[4,5-c]quinolin-2-one (1:1 mixture)

[00641] A mixture of 8-bromo-7-fluoro-1-[(1R,3R)-3-methoxycyclopentyl]-3H-imidazo[4,5-c]quinolin-2-one:8-bromo-7- fluoro-1-[(1S,3S)-3-methoxycyclopentyl]-3H-imidazo[4,5-c]quinolin-2-one (1:1 mixture) (2.8 g, 7.33 mmol), hydroxide sodium hydroxide (440 mg, 11.00 mmol), tetrabutylammonium bromide (240 mg, 0.75 mmol) and methyl iodide (1.6 g, 11.27 mmol) in DCM (150 mL) and water (100 mL) was stirred for 12 hours at room temperature. The resulting mixture was concentrated in vacuo and the residue triturated with water. The solids were collected by filtration and dried to provide the desired material as a white solid (2.5g, 86%). NMR spectrum: 1H NMR (300 MHz, DMSO-d6) δ 1.76 - 1.86 (1H, m), 2.11 - 2.32 (4H, m), 2.41 - 2.44 (1H , m), 3.27 (3H, s), 3.30 (3H, s), 4.12 - 4.15 (1H, m), 5.38 - 5.45 (1H, m), 7, 96 (1H, d), 8.53 (1H, d), 8.94 (1H, s). Mass spectrum: m/z (ES+)[M+H]+ = 394. Intermediate Y2: 8-bromo-7-fluoro-1-[(1R ,3R )-3-methoxycyclopentyl]-3H-imidazo[ 4,5-c]quinolin-2-one and 8-bromo-7-fluoro-1-[(1 S ,3 S )-3-methoxycyclopentyl]-3H-imidazo[4,5-c]quinolin-2- one (1:1 mix)

[00642] A mixture of 6-bromo-7-fluoro-4-[[(1R,3R)-3-methoxycyclopentyl]amino]quinoline-3-carboxylic acid: 6-bromo-7-fluoro-4-[[ (1S,3S)-3-methoxycyclopentyl]amino]quinoline-3-carboxylic acid (1:1 mixture) (2.9 g, 7.53 mmol) and triethylamine (2.3 g, 22.73 mmol) in DMA ( 20 mL) was stirred at room temperature for 30 minutes. Diphenyl phosphorazidate (2.5 g, 9.09 mmol) was added and the resulting solution was stirred for 2 hours at 60 °C. The reaction mixture was allowed to cool and the solids were collected by filtration. The solid was dried in an oven under reduced pressure to provide the desired material as a white solid (2.8g, 97%). NMR spectrum: 1H NMR (300 MHz, DMSO-d6) δ 1.78 - 1.88 (1H, m), 2.11 - 2.31 (4H, m), 2.41 - 2.45 (1H , m), 3.27 (3H, s), 4.08 - 4.15 (1H, m), 5.34 - 5.39 (1H, m), 7.92 (1H, d), 8, 51 (1H, d), 8.68 (1H, s). Mass spectrum: m/z (ES+)[M+H]+ = 380. Intermediate Y3: 6-Bromo-7-fluoro-4-[[(1R ,3R )-3-methoxycyclopentyl]amino]quinoline acid -3-carboxylic acid and 6-bromo-7-fluoro-4-[[(1 S ,3 S )-3-methoxycyclopentyl]amino]quinoline-3-carboxylic acid (1:1 mixture)

[00643] A mixture of ethyl 6-bromo-7-fluoro-4-[[(1R,3R)-3-methoxycyclopentyl]amino]quinoline-3-carboxylate:6-bromo-7-fluoro-4-[[ Ethyl (1S,3S)-3-methoxycyclopentyl]amino]quinoline-3-carboxylate (1:1 mixture) (3.4 g, 8.23 mmol) and 2N sodium hydroxide (12 mL) in MeOH (15 mL ) and THF (15 mL) was stirred for 12 hours at room temperature. The pH of the solution was adjusted to 3 with 1M HCl and the resulting solid collected by filtration and dried to provide the desired material as a white solid (2.9g, 91%). NMR spectrum: 1H NMR (300 MHz, DMSO-d6) δ 1.61 - 1.71 (2H, m), 1.76 - 1.86 (1H, m), 1.92 - 2.03 (1H , m), 2.11 - 2.26 (2H, m), 3.21 (3H, s), 3.86 - 3.96 (1H, m), 4.56 - 4.64 (1H, m ), 7.70 (1H, d), 8.56 (1H, d), 8.88 (1H, s), 13.31 (1H, s). Mass spectrum: m/z (ES+)[M+H]+ = 383. Intermediate Y4:6-bromo-7-fluoro-4-[[(1R ,3R )-3-methoxycyclopentyl]amino]quinoline- Ethyl 3-carboxylate and Ethyl 6-bromo-7-fluoro-4-[[(1S,3S)-3-methoxycyclopentyl]amino]quinoline-3-carboxylate (1:1 mixture)

[00644] A mixture of ethyl 6-bromo-4-chloro-7-fluoroquinoline-3-carboxylate (2 g, 6.01 mmol), (1R,3R)-3-methoxycyclopentanamine hydrochloride and (1S, 3S)-3-methoxycyclopentanamine (1:1 mixture) (1.4 g, 9.21 mmol) and DIPEA (1.6 g, 12.38 mmol) in DMA (10 mL) was stirred for 2 h at 80° W. The reaction mixture was allowed to cool and the residue was triturated with water. The solids were collected by filtration and dried to provide the desired material as a white solid (2.4g, 97%). Mass spectrum: m/z (ES+)[M+H]+ = 411.

[00645] The preparation of ethyl 6-bromo-4-chloro-7-fluoroquinoline-3-carboxylate has been described previously.Examples 64 and 65 1-[(1 R ,3 R )-3-Methoxycyclopentyl]-3-methyl -8-[6-[3-(1 -piperidyl)propoxy]-3-pyridyl]imidazo[4,5-c]quinolin-2-one and 1-[(1S,3S)-3-Methoxycyclopentyl]- 3-methyl-8-[6-[3-(1-piperidyl)propoxy]-3-pyridyl]imidazo[4,5-c]quinolin-2-one

[00646] A mixture of 3-(piperidin-1-yl)propan-1-ol (175 mg, 1.22 mmol) and NaH (122 mg, 3.06 mmol) in THF (10 mL) was stirred under nitrogen at 0 °C for 30 minutes, then 8-(6-fluoro-3-pyridyl)-1-[(1R,3R)-3-methoxycyclopentyl]-3-methyl-imidazo[4,5-c ]quinolin-2-one:8-(6-fluoro-3-pyridyl)-1-[(1S,3S)-3-methoxycyclopentyl]-3-methylimidazo[4,5-c]quinolin-2-one (1:1 mixture) (400 mg, 1.02 mmol). The resulting mixture was stirred at room temperature for 1 h then quenched with water (50 mL), extracted with EtOAc (3 x 50 mL), the organic layer dried over Na 2 SO 4 , filtered and evaporated to give a yellow oil. The crude liquid was triturated with heptane to provide the desired mixed isomer material (350 mg, 66.6%) as a yellow solid. The racemic mixture was purified by preparative chiral HPLC on an AD column, eluting with 10% isopropyl alcohol in hexane (modified with 0.1% diethylamine) as eluent, and the fractions containing the separated isomers were evaporated until completely dry.

[00647] Example 64: Isomer 1 (120 mg) NMR spectrum: 1H NMR (300 MHz, MeOH-d4) δ 1.61 - 1.71 (2H, m), 1.76 - 1.86 (1H, m), 1.92 - 2.03 (1H, m), 2.11 - 2.26 (2H, m), 3.21 (3H, s), 3.86 - 3.96 (1H, m) , 4.56 - 4.64 (1H, m), 7.70 (1H, d), 8.56 (1H, d), 8.88 (1H, s), 13.31 (1H, s). Mass spectrum: m/z (ES+)[M+H]+ = 516.

[00648] Example 65: Isomer 2 (120 mg) NMR spectrum: 1H NMR (300 MHz, MeOH-d4) δ 1.53 (2H, q), 1.67 (4H, p), 1.89 - 2 .14 (3H, m), 2.23 - 2.41 (3H, m), 2.47 - 2.71 (8H, m), 3.40 (3H, s), 3.58 (3H, s ), 4.17-4.18 (1H, m), 4.41 (2H, t), 5.62 (1H, p), 6.94 (1H, d), 7.88 (1H, d) , 8.02 - 8.17 (2H, m), 8.38 (1H, d), 8.51 (1H, d), 8.76 (1H, s). Mass spectrum: m/z (ES+)[M+H]+ = 516.

[00649] The following compounds were prepared analogously from 8-(6-fluoro-3-pyridyl)-1-[(1R,3R)-3-methoxycyclopentyl]-3-methyl-imidazo[4,5 -c]quinolin-2-one:8-(6-fluoro-3-pyridyl)-1-[(1S,3S)-3-methoxycyclopentyl]-3-methyl-imidazo[4,5-c]quinolin-2 -one (1:1 mixture) and the appropriate alcohol. * The reaction was stirred at room temperature for 5 hours. The isomers were separated by preparative chiral HPLC on an AD column, eluting with 10% isopropyl alcohol in hexane (modified with 0.1% diethylamine) as eluent.

[00650] Example 66: Isomer 1 (105 mg) NMR spectrum: 1H NMR (300 MHz, CDCl3) δ 1.91 - 2.05 (5H, m), 2.14-2.18 (2H, m) , 2.22 - 2.46 (3H, m), 2.52 - 2.83 (8H, m), 3.39 (3H, s), 3.62 (3H, s), 4.20 (1H ,p), 4.47 (2H, t), 5.62 (1H, q), 6.91 (1H, d), 7.83 (1H, d), 7.94 (1H, d), 8 .24 (1H, d), 8.36 (1H, d), 8.53 (1H, d), 8.73 (1H, s). Mass spectrum: m/z (ES+)[M+H]+ = 502.

[00651] Example 67: Isomer 2 (105 mg) NMR spectrum: 1H NMR (300 MHz, CDCl3) δ 1.80-2.00 (5H, m), 2.12-2.18 (2H, m) , 2.352.55 (3H, m), 2.63-2.83 (8H, m), 3.40 (3H, s), 3.62 (3H, s), 4.20 (1H, t), 4.47 (2H, t), 5.61 (1H, p), 6.91 (1H, d), 7.83 (1H, d), 7.94 (1H, d), 8.25 (1H , d), 8.36 (1H, d), 8.53 (1H, d), 8.73 (1H, s). Mass spectrum: m/z (ES+)[M+H]+ = 502.

[00652] The preparation of 8-(6-fluoro-3-pyridyl)-1-[(1R,3R)-3-methoxycyclopentyl]-3-methyl-imidazo[4,5-c]quinolin-2-one: 8-(6-fluoro-3-pyridyl)-1-[(1S,3S)-3-methoxycyclopentyl]-3-methyl-imidazo[4,5-c]quinolin-2-one (1:1 mixture) is Described below. Intermediate O5: 8-(6-Fluoro-3-pyridyl)-1-[(1R,3R)-3-methoxycyclopentyl]-3-methyl-imidazo[4,5-c]quinolin-2-one and 8- (6-fluoro-3-pyridyl)-1-[(1S,3S)-3-methoxycyclopentyl]-3-methyl-imidazo[4,5-c]quinolin-2-one (1:1 mixture)

[00653] A mixture of 8-bromo-1-[(1R,3R)-3-methoxycyclopentyl]-3-methylimidazo[4,5-c]quinolin-2-one:8-bromo-1-[(1S, 3S)-3-methoxycyclopentyl]-3-methylimidazo[4,5-c]quinolin-2-one (1:1 mixture) (1.5 g, 3.99 mmol), (6-fluoropyridin-3-yl) acid )boronic acid (0.674 g, 4.78 mmol) and chloro(2-dicyclohexylphosphine-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1 '-biphenyl)]palladium(II) (0.314 g, 0.40 mmol) in dioxane:water (10:1 mixture) (16.5 mL) was heated to 120 °C for 45 minutes in the microwave reactor, then allowed to cool and concentrated in vacuo. The crude product was purified by FCC, gradient elution from 0 to 10% MeOH in DCM, providing the desired material as a yellow solid (1.20 g, 77%). NMR spectrum: 1H NMR (400 MHz, CDCl3) δ 1.91 - 1.99 (1H, m), 2.21 - 2.36 (3H, m), 2.58 - 2.78 (2H, m ), 3.38 (3H, s), 3.62 (3H, s), 4.15 - 4.17 (1H, m), 5.52 - 5.65 (1H, m), 7.12 ( 1H, dd), 7.83 (1H, dd), 8.13 (1H, td), 8.31 (1H, d), 8.40 (1H, d), 8.59 (1H, d), 8.76 (1H, s). Mass spectrum: m/z (ES+)[M+H]+ = 393.

[00654] The preparation of 8-bromo-1-[(1R,3R)-3-methoxycyclopentyl]-3-methylimidazo[4,5-c]quinolin-2-one:8-bromo-1-[(1S, 3S)-3-methoxycyclopentyl]-3-methylimidazo[4,5-c]quinolin-2-one (1:1 mixture) has been previously described. Examples 68 and 69 8-[6-[3-(Dimethylamino)propoxy]-2-fluoro-3-pyridyl]-1-[(1 R ,3 R )-3-methoxycyclopentyl]-3-methyl-imidazo[4 ,5-c]quinolin-2-one and 8-[6-[3-(dimethylamino)propoxy]-2-fluoro-3-pyridyl]-1-[(1 S ,3 S )-3-methoxycyclopentyl]- 3-methyl-imidazo[4,5-c]quinolin-2-one

[00655] Chloro(2-dicyclohexylphosphine-2',4',6'-triisopropyl-1,1-biphenyl)[2-(2-amino-1,1-biphenyl)]palladium (II) (107 mg , 0.13 mmol) was added to 3-[6-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl]oxy-N ,N-dimethylpropan-1-amine (474 mg, 1.46 mmol), 8-bromo-1-[(1R,3R)-3-methoxycyclopentyl]-3-methylimidazo[4,5-c]quinolin-2- one:8-bromo-1-[(1S,3S)-3-methoxycyclopentyl]-3-methylimidazo[4,5-c]quinolin-2-one (1:1 mixture) (500 mg, 1.33 mmol) and cesium carbonate (1299 mg, 3.99 mmol) in 1,4-dioxane (10 mL) and water (2.5 mL). The resulting mixture was stirred at 80 °C for 5 hours, then allowed to cool. The crude product was purified by C18-FCC, gradient elution from 5 to 50% MeOH in water, providing the desired material as a mixture of isomers (350 mg, 53.4%). The racemic mixture was purified by preparative chiral HPLC on a Chiralcel IC column, eluting with isopropyl alcohol, and the fractions containing the separated isomers were evaporated until completely dry.

[00656] Example 68: Isomer 1 (50 mg) NMR spectrum: 1H NMR (300 MHz, MeOH-d4) δ 1.90-1.96 (1H, m), 2.12-2.13 (2H, m), 2.202.31 (3H, m), 2.47-2.50 (1H, m), 2.54 (6H, s), 2.68-2.70 (1H, m), 2.78 - 2.90 (2H, m), 3.36 (3H, s), 3.60 (3H, s), 4.17-4.18 (1H, m), 4.43 (2H, t), 5.55 - 5.67 (1H, m), 6.89 (1H, d), 7.80 - 7.91 (1H, m), 8.07 - 8.20 (2H, m), 8, 48 (1H, s), 8.82 (1H, s). Mass spectrum: m/z (ES+)[M+H]+ = 494.

[00657] Example 69: Isomer 2 (45 mg) (contaminated with 0.38 equivalents of diethylamine) NMR spectrum: 1H NMR (300 MHz, MeOH-d4) δ 1.93-1.95 (1H, m), 2.29 - 2.51 (6H, m), 2.60 - 2.77 (2H, m), 2.95 (6H, s), 3.36 -3.38(4H, s), 3, 60 (3H, s), 4.17-4.18 (1H, m), 4.48 (2H, t), 5.62-5.63 (1H, m), 6.92 (1H, d) , 7.85 (1H, d), 8.15-8.20 (2H, m), 8.48 (1H, s), 8.82 (1H, s). Mass spectrum: m/z (ES+)[M+H]+ = 494.

[00658] The preparation of 8-bromo-1-[(1R,3R)-3-methoxycyclopentyl]-3-methylimidazo[4,5-c]quinolin-2-one:8-bromo-1-[(1S, 3S)-3-methoxycyclopentyl]-3-methylimidazo[4,5-c]quinolin-2-one (1:1 mixture) has been described previously. Examples 70 and 71 8-[6-[3-(dimethylamino)propoxy] -3-pyridyl]-7-fluoro-1-[(1R,3S)-3-methoxycyclopentyl]-3-methyl-imidazo[4,5-c]quinolin-2-one and 8-[6-[ 3-(dimethylamino)propoxy]-3-pyridyl]-7-fluoro-1-[(1 S ,3 R )-3-methoxycyclopentyl]-3-methyl-imidazo[4,5-c]quinolin-2-one

[00659] 8-Bromo-7-fluoro-1-[(1R,3S)-3-methoxycyclopentyl]-3-methyl-imidazo[4,5-c]quinolin-2-one:8-bromo-7-fluoro -1-[(1S,3R)-3-methoxycyclopentyl]-3-methyl-imidazo[4,5-c]quinolin-2-one (1:1 mixture) (500 mg, 1.27 mmol), N, N-dimethyl-3-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl]oxypropan-1-amine (284 mg, 1.27 mmol) and chloro(2-dicyclohexylphosphine-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (200 mg, 0.25 mmol) was suspended in a mixture of dioxane:water (10:1 mixture, 20 mL) and Cs2CO3 (826 mg, 2.54 mmol) was added. The reaction was heated to 120°C for 1 hour in the microwave reactor then allowed to cool. The reaction mixture was evaporated to dryness and redissolved in EtOAc (100 mL), washed sequentially with water (2 x 20 mL), the organic layer dried with Na 2 SO 4 , filtered and evaporated to give the crude product. The crude product was purified by preparative HPLC, using mixtures of water of decreasing polarity (containing 0.03% NH 3 ) and MeCN as eluents, to provide the desired material in a racemic mixture. The mixture was purified by preparative chiral HPLC on a Chiralpak IA column, isocratically eluting with 10% IPA in heptane (modified with 0.2% diethylamine) as eluent to provide the two separate isomers.

[00660] Example 70: Isomer 1 (250 mg) NMR spectrum: 1H NMR (400 MHz, DMSO-d6) δ 1.83 - 2.06 (5H, m), 2.14 - 2.19 (6 H, s), 2.26 - 2.51 (5H, m), 3.02 - 3.07 (3H, s), 3.47 - 3.64 (3H, s), 3.86 - 3.96 (1H, m), 4.33 - 4.41 (2H, m), 5.26 - 5.40 (1H, m), 6.94 - 7.01 (1H, m). d), 7.89 - 7.97 (1H, d), 7.98 - 8.06 (1H, m), 8.39 - 8.49 (2H, m), 8.92 - 8 .97 (1H, s). Mass spectrum: m/z (ES+)[M+H]+ = 494.

[00661] Example 71: Isomer 2 (250 mg) NMR spectrum: 1H NMR (400 MHz, DMSO-d6) δ 1.83 - 2.08 (5 H, m), 2.13 - 2.18 (5 H, s), 2.24 - 2.56 (4H, m), 3.02 - 3.07 (3H, s), 3.50 - 3.55 (3H, s), 3.85 - 3.96 (1H, m), 4.33 - 4.41 (2H, m), 5.25 - 5.39 (1H, m), 6.94 - 7.01 (1H, m). m), 7.87 - 7.95 (1H, m), 7.97 - 8.05 (1H, m), 8.35 - 8.50 (2H, m), 8.91 - 8 .96 (1H, s). Mass spectrum: m/z (ES+)[M+H]+ = 494.

[00662] The preparation of 8-bromo-7-fluoro-1-[(1R,3S)-3-methoxycyclopentyl]-3-methyl-imidazo[4,5-c]quinolin-2-one and 8-bromo- 7-Fluoro-1-[(1S,3R)-3-methoxycyclopentyl]-3-methyl-imidazo[4,5-c]quinolin-2-one (1:1 mixture) is described below: Intermediate Z1: 8- Bromo-7-fluoro-1-[(1R,3S)-3-methoxycyclopentyl]-3-methyl-imidazo[4,5-c]quinolin-2-one and 8-bromo-7-fluoro-1-[ (1 S ,3 R )-3-methoxycyclopentyl]-3-methyl-imidazo[4,5-c]quinolin-2-one (1:1 mixture)

[00663] NaH (0.213 g, 8.88 mmol) was added portionwise to 8-bromo-7-fluoro-1-[(1R,3S)-3-hydroxycyclopentyl]-3H-imidazo[4,5-c] quinolin-2-one:8-bromo-7-fluoro-1-[(1S,3R)-3-hydroxycyclopentyl]-3H-imidazo[4,5-c]quinolin-2-one (1:1 mixture) ( 1.3 g, 3.55 mmol) in DMF (10 mL) at -20 °C under nitrogen and the resulting mixture stirred at 0 °C for 30 minutes. Methyl iodide (0.444 mL, 7.10 mmol) was added dropwise to the mixture at -20 °C under nitrogen and the resulting mixture was stirred at room temperature for 16 hours. The reaction mixture was poured into water (20ml), the solid filtered and dried to give the desired material as a brown solid (1.30g, 93%). NMR spectrum: 1H NMR (400 MHz, DMSO-d6) δ 1.96-2.02 (3H, t), 2.22-2.51 (3H, m), 3.30-3.32 (3H, s), 3.97 (1H, m), 5.26-5.31 (1H, m), 7.89-7.52 (1H, d), 8.74 (1H , d), 8.93 (1H, s). Mass spectrum: m/z (ES+)[M+H]+ = 396. Intermediate Z2: 8-Bromo-7-fluoro-1-[(1 R ,3 S )-3-hydroxycyclopentyl]-3H-imidazo[ 4,5-c]quinolin-2-one and 8-bromo-7-fluoro-1-[(1 S ,3 R )-3-hydroxycyclopentyl]-3H-imidazo[4,5-c]quinolin-2- one (1:1 mix)

[00664] A mixture of triethylamine (2.105 mL, 15.10 mmol) and 6-bromo-7-fluoro-4-[[(1R,3S)-3-hydroxycyclopentyl]amino]quinoline-3-carboxylic acid:6 -bromo-7-fluoro-4-[[(1S,3R)-3-hydroxycyclopentyl]amino]quinoline-3-carboxylic acid (1:1 mixture) (2 g, 5.03 mmol) in DMF (10 mL) was stirred for 1 hour. Diphenyl phosphorazidate (1.663 g, 6.04 mmol) was added and the resulting solution was stirred overnight at 60 °C. The reaction mixture was poured into water, the solids collected by filtration and dried to give the desired material as a yellow solid (1.3g, 71%). NMR spectrum: 1H NMR (400 MHz, DMSO-d6) δ 1.88 (2H, dt), 1.97 - 2.10 (1H, m), 2.17 (1H, m), 2.38 ( 2H, m), 4.23 - 4.30 (1H, m), 5.27 (1H, m), 7.88 (1H, m), 8.69 (1H, s), 8.80 (1H, m) , d), 11.77 (1H, s). Mass spectrum: m/z (ES+)[M+H]+ = 366. Intermediate Z3: 6-Bromo-7-fluoro-4-[[(1 R ,3 S )-3-hydroxycyclopentyl]amino]quinoline acid -3-carboxylic acid and 6-bromo-7-fluoro-4-[[(1 S ,3 R )-3-hydroxycyclopentyl]amino]quinoline-3-carboxylic acid (1:1 mixture)

[00665] A mixture of ethyl 6-bromo-7-fluoro-4-[[(1R,3S)-3-hydroxycyclopentyl]amino]quinoline-3-carboxylate:6-bromo-7-fluoro-4-[[ Ethyl (1S,3R)-3-hydroxycyclopentyl]amino]quinoline-3-carboxylate (1:1 mixture) (3 g, 7.55 mmol) and sodium hydroxide (0.604 g, 15.10 mmol) in THF ( 10 mL) and water (5 mL) was stirred for 16 hours at 60 °C. The organic phases were removed in vacuo and the pH of the resulting mixture was adjusted to 6-7 with 2M HCl. The resulting solid was collected by filtration and dried to provide the desired material as a gray solid (2.0g, 72%). NMR spectrum: 1H NMR (400 MHz, DMSO-d6) δ 1.68 - 1.82 (3H, m), 1.90 - 1.98 (1H, m), 2.26 (2H, m), 2.51 (4H, s), 4.26 (1H, s), 4.68 (1H, s), 7.86 (1H, d), 8.62 (1H, d), 8.93 (1H , s), 10.95 (1H, s). Mass spectrum: m/z (ES+)[M+H]+ = 369.Intermediate Z4:6-bromo-7-fluoro-4-[[(1R ,3S )-3-hydroxycyclopentyl]amino]quinoline- Ethyl 3-carboxylate and Ethyl 6-bromo-7-fluoro-4-[[(1S,3R)-3-hydroxycyclopentyl]amino]quinoline-3-carboxylate (1:1 mixture)

[00666] DIPEA (3.94 mL, 22.55 mmol) was added to a mixture of cis-3-aminocyclopentanol hydrochloride (1.49 g, 10.83 mmol) and 6-bromo-4-chloro-7 Ethyl -fluoroquinoline-3-carboxylate (3 g, 9.02 mmol) in DMA (20 mL) under nitrogen and the resulting mixture was stirred at 100°C for 6 hours. The reaction mixture was poured into water (50ml) and the solid filtered and dried to give the desired material as a brown oil (3.0g, 84%). NMR spectrum: 1H NMR (400 MHz, DMSO-d6) δ 1.35 (3H, t), 1.67 (1H, d), 1.72 - 1.79 (2H, m), 1.81 - 1.92 (1H, m), 1.96 (3H, s), 2.19 (2H, ddt), 2.79 (3H, s), 2.95 (3H, s), 3.08 (1H , d), 4.23 (1H, s), 4.33 (2H, q), 4.45 (1H, s), 4.83 (1H, s), 7.69 (1H, dd), 8 .52 (1H, d), 8.85 (1H, s), 9.25 (1H, d). Mass spectrum: m/z (ES+)[M+H]+ = 397.

[00667] The preparation of ethyl 6-bromo-4-chloro-7-fluoroquinoline-3-carboxylate has been previously described.

BIOLOGICAL TESTS

[00668] The following assays were used to measure the effects of the compounds of the present invention: a) cellular potency assay against ATM; b) cellular potency assay against PI3K; c) cellular potency assay against mTOR; d) cellular potency assay against ATR; e) mouse xenograft model. When describing the tests, in general:

[00669] i. The following abbreviations were used: 4NQO = 4-N- nitroquinoline oxide; Ab = antibody; BSA = bovine serum albumin; CO2 = carbon dioxide; DMEM = Dulbecco's Modified Eagle's Medium; DMSO = dimethylsulfoxide; EDTA = ethylenediaminetetraacetic acid; EGTA = ethylene glycol tetracetic acid; ELISA = immunoenzymatic assay; EMEM = Eagle's Minimum Essential Medium; FBS = fetal bovine serum h = hour(s); HRP = horseradish peroxidase; i.p. = intraperitoneal; PBS = phosphate buffered saline; PBST = Phosphate Buffered Saline/Tween; TRIS = Tris(hydroxymethyl)aminomethane; MTS reagent: [3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, inner salt, and an electron coupling reagent, PMS (phenazine methosulfate); s.c. = subcutaneously.

[00670] ii. IC50 values were calculated using a smart fit model in Genedata. The IC50 value was the concentration of the test compound that inhibited 50% of the biological activity.

Test a): Cellular power against ATM Rationale:

[00671] Cellular irradiation induces DNA double-stranded breaks and rapid intermolecular autophosphorylation of serine 1981 that causes dimer dissociation and initiates ATM kinase activity in the cell. Most ATM molecules in the cell are rapidly phosphorylated at this site after radiation doses of only 0.5 Gy, and binding of a phosphospecific antibody is detectable after introducing only a few double-stranded DNA breaks into the cell.

[00672] The rationale of the pATM assay is to identify ATM inhibitors in cells. HT29 cells are incubated with test compounds for 1 hour before X-ray irradiation. One hour later, cells are fixed and stained for pATM (Ser1981). Fluorescence is read on the Arrayscan imaging platform.

Method details:

[00673] HT29 cells (ECACC no 85061109) were seeded in assay plates with 384 wells (Costar no 3712) at a density of 3500 cells/well in 40 μL of EMEM medium, containing 1% L-glutamine and 10% FBS, and allowed to adhere overnight. The following morning, compounds of Formula (I) in 100% DMSO were added to assay plates by acoustic dispensing. After a 1 hour incubation at 37°C and 5% CO 2 , plates (up to 6 at a time) were irradiated using the X-RAD 320 (PXi) instrument with ~600 cGy equivalent. The plates were returned to the incubator for another 1 hour. Next, cells were fixed by adding 20 μL of 3.7% formaldehyde in PBS solution and incubated for 20 minutes at room temperature before being washed with PBS 50 μL/well using a Biotek EL405 plate washer. Then, 20 μL of 0.1% Triton X100 in PBS were added and incubated for 20 minutes at room temperature to permeabilize the cells. Then the plates were washed once more with PBS 50 µL/well using a Biotek EL405 plate washer.

[00674] Phospho-ATM Ser1981 antibody (Millipore on MAB3806) was diluted 10000 times in PBS, containing polysorbate/Tween 0.05% and BSA 3%, and 20 μL were added to each well and incubated overnight at room temperature The next day, the plates were washed three times with PBS 50 μL/well, using a Biotek EL 405 plate washer, then 20 μL of solution with the secondary Ab, containing rabbit anti-IgG, produced in goat and Alexa Fluor® 488 conjugate, diluted 500 times (Life Technologies, A11001) and Hoeschst dye 0.002 mg/mL (Life Technologies no H-3570), in PBS containing 0.05% polysorbate/Tween and 3% BSA, were added. After 1 hour of incubation at room temperature, the plates were washed three times with PBS 50 µL/well using a Biotek EL 405 plate washer and sealed and kept in PBS at 4°C until read. Plates were read with an ArrayScan VTI instrument, using an XF53 filter with a 10X objective. A two-laser setup was used to analyze nuclear staining with Hoeschst (405 nm) and staining on pSer1981 secondary antibody (488 nm).

Test b): Cellular power against ATR Rationale:

[00675] ATR is a PI 3 kinase-related kinase that phosphorylates multiple substrates on serine or threonine residues in response to DNA damage or replication blocks. Chk1, a downstream protein kinase of ATR, plays a key role in controlling DNA damage checkpoints. Activation of Chk1 involves phosphorylation of Ser317 and Ser345 (the latter considered to be the preferred target for phosphorylation/activation by ATR). This cellular assay aimed to assess the inhibition of ATR kinase, measuring a decrease in phosphorylation of Chk1 (Ser 345) in HT29 cells, after treatment with a compound of Formula (I) and the UV mimetic 4NQO (Sigma no N8141).

Method details:

[00676] HT29 cells (ECACC no 85061109) were seeded in assay plates with 384 wells (Costar no 3712) at a density of 6000 cells/well in 40 μL of EMEM medium, containing 1% L-glutamine and 10% FBS FBS, and allowed to adhere overnight. The following morning, the compound of Formula (I) in 100% DMSO was added to the assay plates by acoustic dispensing. After 1 hour of incubation at 37 °C and 5% CO2, 40 nL of 3 mM 4NQO in 100% DMSO were added to the wells by acoustic dispensing, except for minimal control wells that were left untreated with 4NQO to generate a control of 4NQO. null answer. Plates were returned to the incubator for an additional 1 hour. Then, the cells were fixed by adding 20 μL of 3.7% formaldehyde in PBS solution and incubated for 20 minutes at room temperature. Then, 20 μL of 0.1% Triton X100 in PBS were added and incubated for 10 minutes at room temperature to permeabilize the cells. Then, the plates were washed once with PBS 50 µL/well using a Biotek EL 405 plate washer.

[00677] The antibody Phospho-Chk1 Ser 345 (Cell Signaling Technology No. 2348) was diluted 150 times in PBS, containing polysorbate/Tween 0.05%, and 15 μL were added to each well and incubated overnight at temperature environment. The next day, the plates were washed three times with PBS 50 μL/well, using a Biotek EL 405 plate washer, then 20 μL of secondary Ab solution, containing rabbit anti-IgG, produced in goat and conjugated to Alexa Fluor 488, diluted 500-fold (Molecular Probes No. A-11008), and Hoeschst dye 0.002 mg/ml (Molecular Probes No. H-3570), in PBST, were added. After 2 hours of incubation at room temperature, the plates were washed three times with PBS 50 µL/well using a Biotek EL 405 plate washer and closed with black plate seals until readable. The plates were read with an ArrayScan VTI instrument, using an XF53 filter with a 10X objective. A two-laser setup was used to analyze nuclear staining with Hoeschst (405 nm) and staining on the pChk1 secondary antibody (488 nm).

Test c): Cellular power against PI3K Rationale:

[00678] This assay was used to measure the inhibition of PI3K-α in cells. PDK1 was identified as the upstream activation loop kinase of protein kinase B (Akt1), which is essential for PKB activation. Activation of the enzyme lipid kinase phosphoinositide 3 kinase (PI3K) is critical for activation of PKB by PDK1.

[00679] Upon stimulation of receptor tyrosine kinase ligands, PI3K is activated and converts PIP2 to PIP3, which is bound by the PH domain of PDK1 resulting in the recruitment of PDK1 to the plasma membrane where it phosphorylates AKT to Thr308 in the loop of activation.

[00680] The purpose of this mode of action assay in cells is to identify compounds that inhibit PDK activity or PDK1 recruitment to the membrane by inhibiting PI3K activity. Phosphorylation of phospho-Akt (T308) in BT474c cells after treatment with compounds for 2 hours is a direct measure of PDK1 activity and an indirect measure of PI3K activity.

Method details:

[00681] BT474 cells (human ductal breast carcinoma, ATCC HTB-20) were seeded in black 384-well assay plates (Costar, No. 3712) at a density of 5600 cells/well in DMEM, containing 10% FBS and glutamine 1%, and allowed to adhere overnight.

[00682] The next morning, compounds in 100% DMSO were added to the assay plates by acoustic dispensing. After 2 hours of incubation at 37 °C and 5% CO2, the medium was aspirated and the cells were lysed with a buffer containing 25 mM Tris, 3 mM EDTA, 3 mM EGTA, 50 mM sodium fluoride, sodium orthovanadate. 2 mM sodium, 0.27M sucrose, 10 mM β-glycerophosphate, 5 mM sodium pyrophosphate, 0.5% Triton X-100 and complete protease inhibitor cocktail tablets (Roche no 04 693 116 001, used 1 tablet per 50 mL of lysis buffer).

[00683] After 20 minutes, cell lysates were transferred to ELISA plates (Greiner #781077), which had previously been coated with a total anti-AKT antibody in PBS buffer, and non-specific binding was blocked with BSA 1 % in PBS containing 0.05% Tween 20. Plates were incubated overnight at 4°C. The next day, the plates were washed with PBS buffer containing 0.05% Tween 20 and further incubated with an anti-phospho AKT T308 monoclonal antibody for 2 hours. Plates were washed again as above before addition of a horse-produced HRP-conjugated anti-mouse secondary antibody. After a 2 hour incubation at room temperature, the plates were washed, and QuantaBlu substrate working solution (Thermo Scientific #15169, prepared according to the supplier's instructions) was added to each well. The developed fluorescent product was stopped after 60 by adding Stop solution to the plates. Plates were analyzed using a Tecan Safire plate reader with excitation and emission wavelengths of 325 nm and 420 nm, respectively. Unless otherwise specified, reagents contained in Cell Signaling's Path Scan Phosphorus AKT Sandwich ELISA Kit (Thr308) (#7144) were used in this ELISA.

Test d): Power cell against mTOR Rationale:

[00684] This assay was used to measure mTOR inhibition in cells. The purpose of the cellular assay of the phospho-AKT mechanism of action using the Acumen Explorer is to identify PI3Kα or mTOR-Rictor (mTOR Rapamycin Non-Sensitive Partner) inhibitors. Inhibition is measured by any decrease in Akt protein phosphorylation at Ser473 (AKT lies downstream of PI3Kα in the signal transduction pathway) in MDA-MB-468 cells after compound treatment. Method details:

[00685] MDA-MB-468 cells (human breast adenocarcinoma, ATCC on HTB 132) were seeded at 1500 cells/well in 40 µL of DMEM containing 10% FBS and 1% glutamine in black flat-bottomed Greiner plates with 384 cavities. Plates with cells were incubated for 18 hours at 37°C in the incubator before receiving compounds of Formula (I) in 100% DMSO using acoustic dispensing. Compounds were administered at a concentration range of 12 points on a randomized plate map. Control cells were generated by administering 100% DMSO (maximum signal) or adding a reference compound (a PI3K-β inhibitor) that completely eliminated the pAKT signal (minimal control). The plates were incubated at 37 °C for 2 hours, when they were then fixed by adding 10 μL of a 3.7% formaldehyde solution. After 30 minutes, the plates were washed with PBS using a Tecan PW384 plate washer. The wells were blocked, and the cells were permeabilized with the addition of 40 mL of PBS, containing 0.5% Tween20 and 1% Marvel™ (dry milk powder), in addition to being incubated for 60 minutes at room temperature. The plates were washed with PBS containing Tween20 0.5% (v/v), and 20 mL of Rabbit Ser473 anti-phospho AKT Ser473 (Cell Signaling Technologies, #3787) in the same PBS-Tween + Marvel™ 1% was added and incubated overnight at 4°C.

[00686] The plates were washed 3 times with PBS + 0.05% Tween 20 using a Tecan PW384. 20 μL of secondary anti-rabbit antibody conjugated to Alexa Fluor 488 (Molecular Probes, in A11008), diluted in PBS + 0.05% Tween20 containing 1% Mar-vel™, was added to each well and incubated for 1 hour at room temperature. Plates were washed three times as before, then 20 µL of PBS was added to each well and the plates closed with a black plate sealing cap.

[00687] The plates were analyzed in an Acumen plate reader as soon as possible, measuring the green fluorescence after laser excitation at 488 nm. Using this system, IC50 values were generated and plaque quality determined by control wells. Reference compounds were tested each time to monitor assay performance.

Test e): Mouse xenograft model Combination with irinotecan

[00688] Male nude mice received the transplant s.c. of SW620 cells (ATCC - CCL-227) to determine the in vivo antitumor activity of ATM inhibitors. 1 x 106 cells in 50% matrigel (BD Bioscience) were injected s.c. on the left flank of the animals. Animals were randomized into groups of 10-15 when tumors reached a volume of ~200-300 mm 3 and treatment was started. The animals received 3 weekly cycles of treatment with the compound. Irinotecan was administered to the animals i.p. once a week and then 24 hours after irinotecan, they received a daily dose on 3 consecutive days perorally of a compound of Formula (I). Tumors were measured twice a week with a caliper, and tumor volume calculated using an elliptical formula (π/6 x width x width x length). Irinotecan was formulated in a solution with 7.5% DMSO/92.5% water for injections. Compounds of Formula (I) were formulated in solution with 10% DMSO/90% Captisol (30% w/v). Captisol was purchased from Cydex Pharmaceuticals (Trademark), β-cyclodextrin suitable for in vivo use and formulations.

Combination with olaparib

[00689] Female nude mice received the transplant s.c. of a patient-derived HBCx-10 tumor fragment to determine the in vivo antitumor activity of ATM inhibitors. Human tumor samples of various histological origins were obtained from patients and established as transplantable xenografts in immunodeficient mice.

[00690] Tumors from the same passage were transplanted subcutaneously into 5-10 mice. When these tumors reached 1000 to 2000 mm3, the donor mice were sacrificed by cervical dislocation, the tumors excised aseptically and dissected and cut into fragments measuring approximately 20 mm3 and transferred to culture medium before engraftment. After anesthetizing the mice, an incision was made in the skin at the level of the interscapular region, and a 20 mm3 tumor fragment was placed in the subcutaneous tissue.

[00691] The animals were randomized into groups of 10-12 when the tumors reached a volume of 62.5-196 mm3 and treatment started. The animals received 8 weekly cycles of treatment with the compound. Olaparib was administered to the animals 7 days a week orally and then, 1 hour before olaparib, the animals received a single daily oral dose of a compound of Formula (I). Tumors were measured twice a week with a caliper, and tumor volume calculated using the formula [length x width2]/2, where length and width constitute the longest and shortest diameter of the tumor, respectively. Olaparib was formulated in a solution with DMSO 10% (w/v)/HP-b-CD (Kleptose) 10% (w/v), water for injections 80%. Compounds of Formula (I) were formulated in solution with 10% DMSO/90% Captisol (30% w/v). Captisol was purchased from Cydex Pharmaceuticals (Trademark), β-cyclodextrin suitable for in vivo use and formulations.

[00692] The test results of Examples 1 and 2, in test e), are shown in Figures 3, 4 and 5. "1x/week" means a dose once a week. "1x/day" is a once daily dose.

[00693] Table 2 shows the test results of the Examples in tests a), b), c) and d). When multiple repeat tests were performed on a given Example, the result reported is the geometric mean. Table 2: Power data for Examples 1 - 71 in tests a) - d)

[00694] Table 3 shows comparative data of some Compounds of CN102399218A and CN102372711A in tests a), b), c) and d). When multiple repeat tests were performed on a given Compound, the result reported is the geometric mean.Table 3: Potency Data for Certain Compounds of CN102399218A and CN102372711A in Tests a) - d)

Claims (14)

1. Compound, characterized by the fact that it has Formula (I): or a pharmaceutically acceptable salt thereof, wherein: Q is a cyclobutyl or cyclopentyl ring, each optionally substituted with a hydroxy or methoxy group, or Q is an oxetanyl, tetrahydrofuranyl or oxanyl ring, each optionally substituted with a group methyl; R1 is methyl; R2 is hydrogen or methyl; or R1 and R2 together form an azetidinyl, pyrrolidinyl or piperidinyl ring; R3 is hydrogen or fluorine; R4 is hydrogen or methyl; and R5 is hydrogen or fluorine. 2. Compound of Formula (I) according to claim 1, or its pharmaceutically acceptable salt, characterized in that Q is cyclobutyl, 1-methoxy-cyclobut-3-yl, 1-hydroxy-cyclobut-3-yl, 3-methoxycyclopent-1-yl, oxetan-3-yl, tetrahydrofuran-3-yl, oxan-3-yl, oxan-4-yl or 4-methyloxan-4-yl. 3. Compound of Formula (I) according to claim 1, or its pharmaceutically acceptable salt, characterized in that Q is 1-methoxy-cyclobut-3-yl, 1-hydroxy-cyclobut-3-yl or oxan- 4-ila. 4. Compound of formula (I) according to claim 1 or claim 2, or its pharmaceutically acceptable salt, characterized in that R1 is methyl and R2 is hydrogen or methyl. 5. Compound of Formula (I) according to any one of the preceding claims, or its pharmaceutically acceptable salt, characterized in that both R3 and R5 are hydrogen. 6. Compound of Formula (I) according to any one of the preceding claims, or its pharmaceutically acceptable salt, characterized in that R4 is methyl. 7. Compound of Formula (I) according to claim 1, or its pharmaceutically acceptable salt, characterized in that: Q is 1-methoxy-cyclobut-3-yl, 1-hydroxy-cyclobut-3-yl, 3 - methoxycyclopent-1-yl, oxetan-3-yl, oxan-3-yl, oxan-4-yl or 4-methyloxan-4-yl; R1 is methyl; R2 is hydrogen or methyl; or R1 and R2 together form an azetidinyl, pyrrolidinyl or piperidinyl ring; R3 is hydrogen or fluorine; R4 is hydrogen or methyl; and R5 is hydrogen or fluorine. 8. Compound of Formula (I) according to claim 1, or its pharmaceutically acceptable salt, characterized in that the compound is selected from the group consisting of: 8-[6-(3-dimethylaminopropoxy)pyridin-3 -yl]-3-methyl-1-(oxan-4-yl)imidazo[5,4-c]quinolin-2-one; 8-[6-(3-dimethylaminopropoxy)pyridin-3-yl]-1-(cis-3-methoxycyclobutyl)-3-methylimidazo[4,5-c]quinolin-2-one; 8-[6-(3-dimethylaminopropoxy)pyridin-3-yl]-7-fluoro-3-methyl-1-(4-methyloxan-4-yl)imidazo[5,4-c]quinolin-2-one; 8-[6-(3-dimethylaminopropoxy)pyridin-3-yl]-3-methyl-1-(oxetan-3-yl)imidazo[5,4-c]quinolin-2-one; 8-[6-(3-dimethylaminopropoxy)pyridin-3-yl]-1-(cis-3-hydroxycyclobutyl)-3-methylimidazo[4,5-c]quinolin-2-one; 8-[6-(3-dimethylaminopropoxy)pyridin-3-yl]-7-fluoro-1-(cis-3-methoxycyclobutyl)-3-methylimidazo[4,5-c]quinolin-2-one; 8-[6-(3-dimethylaminopropoxy)pyridin-3-yl]-3-methyl-1-(4-methyloxan-4-yl)imidazo[5,4-c]quinolin-2-one; 8-[6-(3-dimethylaminopropoxy)pyridin-3-yl]-7-fluoro-3-methyl-1-(oxan-4-yl)imidazo[5,4-c]quinolin-2-one; 8-[6-(3-dimethylaminopropoxy)pyridin-3-yl]-7-fluoro-3-methyl-1-(oxetan-3-yl)imidazo[5,4-c]quinolin-2-one; 8-[6-(3-dimethylaminopropoxy)pyridin-3-yl]-7-fluoro-3-methyl-1-[(3R)-oxan-3-yl]imidazo[5,4-c]quinolin-2- one; 8-[6-(3-dimethylaminopropoxy)pyridin-3-yl]-7-fluoro-3-methyl-1-[(3S)-oxan-3-yl]imidazo[5,4-c]quinolin-2- one; 8-[6-(3-dimethylaminopropoxy)pyridin-3-yl]-1-(cis-3-methoxycyclobutyl)-3H-imidazo[4,5-c]quinolin-2-one; 8-[6-(3-dimethylaminopropoxy)pyridin-3-yl]-1-(oxan-4-yl)-3H-imidazo[4,5-c]quinolin-2-one; 8-[6-[3-(azetidin-1-yl)propoxy]pyridin-3-yl]-1-(cis-3-hydroxycyclobutyl)-3-methylimidazo[4,5-c]quinolin-2-one; 1-(3-cis-hydroxycyclobutyl)-3-methyl-8-[6-(3-pyrrolidin-1-ylpropoxy)pyridin-3-yl]imidazo[4,5-c]quinolin-2-one; 8-[6-(3-dimethylaminopropoxy)pyridin-3-yl]-3-methyl-1-[(3R)-oxan-3-yl]imidazo[5,4-c]quinolin-2-one; 8-[6-(3-dimethylaminopropoxy)pyridin-3-yl]-3-methyl-1-[(3S)-oxan-3-yl]imidazo[5,4-c]quinolin-2-one; 8-[6-(3-dimethylaminopropoxy)-2-fluoropyridin-3-yl]-1-(cis-3-methoxycyclobutyl)-3-methylimidazo[4,5-c]quinolin-2-one; 8-[6-(3-dimethylaminopropoxy)-2-fluoropyridin-3-yl]-7-fluoro-1-(cis-3-methoxycyclobutyl)-3-methylimidazo[4,5-c]quinolin-2-one; 8-[6-(3-dimethylaminopropoxy)-2-fluoropyridin-3-yl]-3-methyl-1-[(3S)-oxan-3-yl]imidazo[5,4-c]quinolin-2-one ; 8-[6-(3-dimethylaminopropoxy)-2-fluoropyridin-3-yl]-3-methyl-1-(oxan-4-yl)imidazo[5,4-c]quinolin-2-one; 8-[6-(3-dimethylaminopropoxy)-2-fluoropyridin-3-yl]-3-methyl-1-[(3R)-oxan-3-yl]imidazo[5,4-c]quinolin-2-one ; 7-Fluoro-3-methyl-8-[6-(3-pyrrolidin-1-ylpropoxy)-3-pyridyl]-1-[(3S)-tetrahydropyran-3-yl]imidazo[4,5-c ]quinolin-2-one; 7-Fluoro-3-methyl-8-[6-(3-pyrrolidin-1-ylpropoxy)-3-pyridyl]-1-[(3S)-tetrahydropyran-3-yl]imidazo[4,5-c ]quinolin-2-one; 8-[6-(3-dimethylaminopropoxy)pyridin-3-yl]-1-[(1R,3R)-3-methoxycyclopentyl]-3-methylimidazo[4,5-c]quinolin-2-one; 8-[6-(3-dimethylaminopropoxy)pyridin-3-yl]-1-[(1S,3S)-3-methoxycyclopentyl]-3-methylimidazo[4,5-c]quinolin-2-one; 7-Fluoro-1-(cis-3-methoxycyclobutyl)-3-methyl-8-[6-(3-pyrrolidin-1-ylpropoxy)pyridin-3-yl]imidazo[4,5-c]quinolin-2- one; 1-(cis-3-methoxycyclobutyl)-3-methyl-8-[6-(3-pyrrolidin-1-ylpropoxy)pyridin-3-yl]imidazo[4,5-c]quinolin-2-one; 3-Methyl-1-[(3S)-oxan-3-yl]-8-[6-(3-pyrrolidin-1-ylpropoxy)pyridin-3-yl]imidazo[5,4-c]quinolin-2- one; 3-Methyl-1-(oxan-4-yl)-8-[6-(3-pyrrolidin-1-ylpropoxy)pyridin-3-yl]imidazo[5,4-c]quinolin-2-one; 3-Methyl-1-[(3S)-oxan-3-yl]-8-[6-(3-piperidin-1-ylpropoxy)pyridin-3-yl]imidazo[5,4-c]quinolin-2- one; 3-Methyl-1-[(3R)-oxan-3-yl]-8-[6-(3-piperidin-1-ylpropoxy)pyridin-3-yl]imidazo[5,4-c]quinolin-2- one; 1-(cis-3-methoxycyclobutyl)-3-methyl-8-[6-(3-piperidin-1-ylpropoxy)pyridin-3-yl]imidazo[4,5-c]quinolin-2-one; 8-[6-[3-(azetidin-1-yl)propoxy]pyridin-3-yl]-3-methyl-1-[(3R)-oxan-3-yl]imidazo[5,4-c]quinoline -2-one; 1-(cis-3-methoxycyclobutyl)-8-[6-(3-pyrrolidin-1-ylpropoxy)pyridin-3-yl]-3H-imidazo[4,5-c]quinolin-2-one; 1-(oxan-4-yl)-8-[6-(3-piperidin-1-ylpropoxy)pyridin-3-yl]-3H-imidazo[4,5-c]quinolin-2-one; 3-Methyl-1-(oxan-4-yl)-8-[6-(3-piperidin-1-ylpropoxy)pyridin-3-yl]imidazo[5,4-c]quinolin-2-one; 8-[6-[3-(azetidin-1-yl)propoxy]pyridin-3-yl]-1-(cis-3-methoxycyclobutyl)-3-methylimidazo[4,5-c]quinolin-2-one; 8-[6-[3-(azetidin-1-yl)propoxy]pyridin-3-yl]-3-methyl-1-(oxan-4-yl)imidazo[5,4-c]quinolin-2-one ; 3-Methyl-8-[6-(3-methylaminopropoxy)pyridin-3-yl]-1-(oxan-4-yl)imidazo[5,4-c]quinolin-2-one; 3-Methyl-8-[6-(3-methylaminopropoxy)pyridin-3-yl]-1-[(3S)-oxan-3-yl]imidazo[5,4-c]quinolin-2-one; and 1-(cis-3-methoxycyclobutyl)-3-methyl-8-[6-(3-methylaminopropoxy)pyridin-3-yl]imidazo[4,5-c]quinolin-2-one; 3-Methyl-8-[6-[3-(methylamino)propoxy]-3-pyridyl]-1-[(3R)-tetrahydropyran-3-yl]imidazo[4,5-c]quinolin-2- one; 8-[6-[3-(dimethylamino)propoxy]-3-pyridyl]-3-methyl-1-[(3R)-tetrahydrofuran-3-yl]imidazo[4,5-c]quinolin-2- one; 8-[6-[3-(dimethylamino)propoxy]-3-pyridyl]-3-methyl-1-[(3S)-tetrahydrofuran-3-yl]imidazo[4,5-c]quinolin-2- one; 1-Cyclobutyl-8-[6-[3-(dimethylamino)propoxy]-3-pyridyl]-3-methylimidazo[4,5-c]quinolin-2-one; 7-Fluoro-3-methyl-8-[6-[3-(1-piperidyl)propoxy]-3-pyridyl]-1-[(3S)-tetrahydropyran-3-yl]imidazo[4,5- c]quinolin-2-one; 8-[6-[3-(dimethylamino)propoxy]-2-fluoro-3-pyridyl]-7-fluoro-3-methyl-1-[(3S)-tetrahydropyran-3-yl]imidazo[4, 5-c]quinolin-2-one; 8-[6-[3-(dimethylamino)propoxy]-2-fluoro-3-pyridyl]-3-methyl-1-[(3S)-tetrahydrofuran-3-yl]imidazo[4,5-c] quinolin-2-one; 8-[6-[3-(dimethylamino)propoxy]-2-fluoro-3-pyridyl]-3-methyl-1-[(3R)-tetrahydrofuran-3-yl]imidazo[4,5-c] quinolin-2-one; 1-Cyclobutyl-8-[6-[3-(dimethylamino)propoxy]-2-fluoro-3-pyridyl]-3-methyl-imidazo[4,5-c]quinolin-2-one; 8-[6-[3-(dimethylamino)propoxy]-2-fluoro-3-pyridyl]-3-methyl-1-(oxetan-3-yl)imidazo[4,5-c]quinolin-2-one; 7-Fluoro-3-methyl-8-[6-[3-(1-piperidyl)propoxy]-3-pyridyl]-1-tetrahydropyran-4-yl-imidazo[4,5-c]quinolin-2 -one; 3-Methyl-8-[6-[3-(1-piperidyl)propoxy]-3-pyridyl]-1-[(3R)-tetrahydrofuran-3-yl]imidazo[4,5-c]quinolin- 2-one; 3-Methyl-8-[6-[3-(1-piperidyl)propoxy]-3-pyridyl]-1-[(3S)-tetrahydrofuran-3-yl]imidazo[4,5-c]quinolin- 2-one; 3-Methyl-1-(oxetan-3-yl)-8-[6-[3-(1-piperidyl)propoxy]-3-pyridyl]imidazo[4,5-c]quinolin-2-one; 1-Cyclobutyl-3-methyl-8-[6-[3-(1-piperidyl)propoxy]-3-pyridyl]imidazo[4,5-c]quinolin-2-one; 1-Cyclobutyl-3-methyl-8-[6-(3-pyrrolidin-1-ylpropoxy)-3-pyridyl]imidazo[4,5-c]quinolin-2-one; 3-Methyl-8-[6-(3-pyrrolidin-1-ylpropoxy)-3-pyridyl]-1-[(3R)-tetrahydropyran-3-yl]imidazo[4,5-c]quinolin-2 -one; 8-[6-[3-(azetidin-1-yl)propoxy]-3-pyridyl]-3-methyl-1-[(3S)-tetrahydropyran-3-yl]imidazo[4,5-c] quinolin-2-one; 8-[2-Fluoro-6-(3-pyrrolidin-1-ylpropoxy)-3-pyridyl]-3-methyl-1-[(3S)-tetrahydropyran-3-yl]imidazo[4,5-c ]quinolin-2-one; 8-[6-[3-(dimethylamino)propoxy]-3-pyridyl]-7-fluoro-1-[(1R,3R)-3-methoxycyclopentyl]-3-methyl-imidazo[4,5-c]quinoline -2-one; 8-[6-[3-(dimethylamino)propoxy]-3-pyridyl]-7-fluoro-1-[(1S,3S)-3-methoxycyclopentyl]-3-methyl-imidazo[4,5-c]quinoline -2-one; 1-[(1R,3R)-3-methoxycyclopentyl]-3-methyl-8-[6-[3-(1-piperidyl)propoxy]-3-pyridyl]imidazo[4,5-c]quinolin-2- one; 1-[(1S,3S)-3-methoxycyclopentyl]-3-methyl-8-[6-[3-(1-piperidyl)propoxy]-3-pyridyl]imidazo[4,5-c]quinolin-2- one; 1-[(1S,3S)-3-methoxycyclopentyl]-3-methyl-8-[6-(3-pyrrolidin-1-ylpropoxy)-3-pyridyl]imidazo[4,5-c]quinolin-2-one ; 1-[(1R,3R)-3-methoxycyclopentyl]-3-methyl-8-[6-(3-pyrrolidin-1-ylpropoxy)-3-pyridyl]imidazo[4,5-c]quinolin-2-one ; 8-[6-[3-(dimethylamino)propoxy]-2-fluoro-3-pyridyl]-1-[(1R,3R)-3-methoxycyclopentyl]-3-methyl-imidazo[4,5-c]quinoline -2-one; 8-[6-[3-(dimethylamino)propoxy]-2-fluoro-3-pyridyl]-1-[(1S,3S)-3-methoxycyclopentyl]-3-methyl-imidazo[4,5-c]quinoline -2-one; 8-[6-[3-(dimethylamino)propoxy]-3-pyridyl]-7-fluoro-1-[(1R,3S)-3-methoxycyclopentyl]-3-methyl-imidazo[4,5-c]quinoline -2-one; and 8-[6-[3-(dimethylamino)propoxy]-3-pyridyl]-7-fluoro-1-[(1S,3R)-3-methoxycyclopentyl]-3-methyl-imidazo[4,5-c] quinolin-2-one. 9. Compound of Formula (I) according to claim 1, characterized in that the compound is 8-[6-(3-dimethylaminopropoxy)-pyridin-3-yl]-3-methyl-1-(oxan -4-yl)imidazo[5,4-c]quinolin-2-one or a pharmaceutically acceptable salt thereof. 10. Compound of Formula (I) according to claim 9, characterized in that the compound is 8-[6-(3-dimethylaminopropoxy)-pyridin-3-yl]-3-methyl-1-(oxan -4-yl)imidazo[5,4-c]quinolin-2-one. 11. Compound of Formula (I) according to claim 10, characterized in that it is in crystalline form that has an X-ray powder pattern with at least two specific 2-theta peaks of 3.9 and 11.6 ° plus or minus 0.2° 2-theta, which were measured using Cu radiation. 12. Pharmaceutical composition, characterized in that it comprises a compound of Formula (I), or its pharmaceutically acceptable salt, as defined in any one of claims 1 to 11 and at least one diluent or pharmaceutically acceptable vehicle. 13. Use of a compound of Formula (I), or its pharmaceutically acceptable salt, according to any one of claims 1 to 11, characterized in that it is for the preparation of a medicine to treat cancer. 14. Use of a compound of Formula (I), or its pharmaceutically acceptable salt, according to claim 13, characterized in that the cancer is selected from the group consisting of colorectal cancer, glioblastoma, gastric cancer, ovarian cancer, diffuse large B-cell lymphoma, chronic lymphocytic leukemia, acute myeloid leukemia, squamous cell carcinoma of the head and neck, breast cancer, triple negative breast cancer, hepatocellular carcinoma, small cell lung cancer, and colon cancer non-small cell lung.